Neurobiology and aetiology

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Neurobiology and aetiology

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Parkinson’s disease: Neurobiology and aetiology
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Neurobiology
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The motor cortex
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Motor activity is controlled by projections that range from the primary motor cortex and the premotor cortical areas of the frontal lobe through to the brainstem and spinal cord.[Patestas & Gartner, 2016] The primary motor cortex has an important function in the execution of distinct, well-defined, voluntary motor activity.[Patestas & Gartner, 2016]
A striking characteristic of the primary motor cortex in humans is that over half of it is associated with the motor activity of the hands, tongue, lips, and larynx, reflecting the manual dexterity and ability for speech possessed by humans.[Patestas & Gartner, 2016] The primary motor cortex also influences the motor control of muscles in the trunk and head regions, as well as control of distal muscles in the upper and lower limbs – i.e., those muscles that control movements of the hands and feet.[Patestas & Gartner, 2016]
 

Patestas MA, Gartner LP. A Textbook of Neuroanatomy, 2nd edition. Hoboken, New Jersey: John Wiley & Sons Inc., 2016.
Amaral DG. The Functional Organization of Perception and Movement. In: Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th edition. New York: McGraw-Hill Companies Inc., 2000.
Purves D, Augustine GJ, Fitzpatrick D, et al. Neuroscience, 4th edition. Sunderland, Massachusetts: Sinauer Associates Inc., 2008.

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The basal ganglia
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Normal motor function is the result of complex and intricate interactions between the basal ganglia, the cerebellum, and the cerebral cortex.[Patestas & Gartner, 2016] The main function of the basal ganglia is to initiate motor activity and to control cortical outputs – indirectly through the thalamus – that relate to motor function.[Patestas & Gartner, 2016]

All four lobes of the cerebrum (frontal, parietal, occipital, temporal), the thalamus and the brainstem contain projections to the ‘input’ nuclei of the basal ganglia – mainly the caudate nucleus and putamen.[Patestas & Gartner, 2016] The caudate nucleus is associated primarily with cognitive function and less so with motor activity, whereas the putamen is associated primarily with motor functions.[Patestas & Gartner, 2016] 

These input nuclei then project to the globus pallidus, which in turn relays the output of the basal ganglia, via the thalamus, to the motor and other areas of the frontal cortex.[Patestas & Gartner, 2016]

In addition to its well-known role in motor function, it is now increasingly realised that the basal ganglia are involved in numerous non-motor functions.[Patestas & Gartner, 2016; Mallet et al., 2007] Disturbances of the basal ganglia can therefore result in impaired cognition, perception, and emotional behaviour.[Patestas & Gartner, 2016; Mallet et al., 2007]
 

 

Mallet L, Schüpbach M, N’Diaye K, et al. Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior. Proc Natl Acad Sci USA 2007; 104 (25): 10661–10666.

Patestas MA, Gartner LP. A Textbook of Neuroanatomy, 2nd edition. Hoboken, New Jersey: John Wiley & Sons Inc., 2016.

DeLong MR. The Basal Ganglia. In: Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th edition. New York: McGraw-Hill Companies Inc., 2000.

Purves D, Augustine GJ, Fitzpatrick D, et al. Neuroscience, 4th edition. Sunderland, Massachusetts: Sinauer Associates Inc., 2008.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology, 12th Edition. John Wiley & Sons, 2009.

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The direct and indirect motor pathways
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Direct motor pathway mechanism (facilitates movement)
The direct motor pathway goes from the striatum to the globus pallidus interna (GPi) via fibres that inhibit GPi activity.[DeLong, 2000] When this occurs, the GPi no longer inhibits the thalamus, which is now able to send an excitatory message to the cortex to initiate movement.[DeLong, 2000] Thus, activity of the direct motor pathway facilitates body movement through the motor neurons.[DeLong, 2000]

Indirect motor pathway mechanism (inhibits movement)
Activity routed to the GPi via the indirect pathway involves several extra steps.[DeLong, 2000] First, impulses go from the striatum to the external segment of the globus pallidus (GPe), then onward to the subthalamic nucleus and the GPi.[DeLong, 2000]
Inhibitory output from the striatum to the GPe shuts down inhibition of the subthalamic nucleus, which then sends excitatory messages to the GPi.[DeLong, 2000] This increases the GPi’s inhibitory activity on the thalamus, which reduces the excitatory output from the thalamus to the cortex.[DeLong, 2000] This results in a lower amount of excitatory activity by the cortex on motor neurons in the body.[DeLong, 2000] Thus, the indirect motor pathway inhibits body movement.[DeLong, 2000]
 

DeLong MR. The Basal Ganglia. In: Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th edition. New York: McGraw-Hill Companies, Inc., 2000.

Kravitz AV, Freeze BS, Parker PR, et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 2010; 466 (7306): 622–626.

Purves D, Augustine GJ, Fitzpatrick D, et al. Neuroscience, 4th edition. Sunderland, Massachusetts: Sinauer Associates Inc., 2008.

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Neurotransmitters and the presynaptic and postsynaptic neurons
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Cells of the nervous system communicate with each other at synapses, either via electrical signals or by the release of messenger molecules called neurotransmitters.[Patestas & Gartner, 2016] Examples of neurotransmitters include: acetylcholine, adrenaline, dopamine, serotonin, glutamate, and histamine.[Patestas & Gartner, 2016]
Neurotransmitters are characterised by five basic qualities:[Patestas & Gartner, 2016] 

  • they are synthesised by presynaptic neurons
  • they reside within synaptic terminals, enclosed in vesicles
  • they are released from presynaptic terminals by way of a calcium-dependent mechanism
  • they bind to specific receptors on the postsynaptic membrane
  • they are inactivated in the synaptic cleft.

Neurotransmitters can either bind to ion channels, in which case they have a direct and immediate effect on post-synaptic function, or they can bind to G-protein-coupled receptors, which results in an indirect and slower effect.[Patestas & Gartner, 2016] For this reason, neurotransmitters falling into the latter category are sometimes referred to as ‘neuromodulators’.[Patestas & Gartner, 2016]
 

 

Patestas MA, Gartner LP. A Textbook of Neuroanatomy, 2nd edition. Hoboken, New Jersey: John Wiley & Sons Inc., 2016.

Kandel ER, Siegelbaum SA. Overview of Synaptic Transmission. In: Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th edition. New York: McGraw-Hill Companies Inc., 2000.

Purves D, Augustine GJ, Fitzpatrick D, et al. Neuroscience, 4th edition. Sunderland, Massachusetts: Sinauer Associates Inc., 2008.

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The role of dopamine in the brain
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Dopamine is an excitatory neurotransmitter present in the neurons of several regions of the central nervous system.[Patestas & Gartner, 2016] The major dopamine-containing area is the corpus striatum, which plays a central role in the coordination of body movements.[Patestas & Gartner, 2016; Purves et al., 2008]
In addition to the corpus striatum, dopamine is also a key neurotransmitter for three other regions:[Patestas & Gartner, 2016; Purves et al., 2008]

  • the substantia nigra pars compacta, the axons of which project to the striatum as part of the dopaminergic nigrostriatal pathway
  • the ventral tegmentum, the axons of which project to the limbic system; the ventral tegmentum constitutes a vital part of the dopaminergic reward system that governs motivation and emotional reinforcement
  • the arcuate nucleus, which regulates the functions of several important hormones and vital physiological functions, such as feeding and cardiovascular function.
     

Patestas MA, Gartner LP. A Textbook of Neuroanatomy, 2nd edition. Hoboken, New Jersey: John Wiley & Sons Inc., 2016.

Purves D, Augustine GJ, Fitzpatrick D, et al. Neuroscience, 4th edition. Sunderland, Massachusetts: Sinauer Associates Inc., 2008.

Kandel ER, Siegelbaum SA. Overview of Synaptic Transmission. In: Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th edition. New York: McGraw-Hill Companies Inc., 2000.

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The pathogenesis of Parkinson’s disease
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Lewy bodies
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A Lewy body is largely composed of misfolded, insoluble α‑synuclein.[Halliday et al., 2014] There are, however, many other components of Lewy bodies, including structural fibril proteins, α‑synuclein-binding proteins, and cellular components normally involved in the degradation and recycling of proteins (the ‘ubiquitin–proteosome’ system).[Halliday et al., 2014]

The presence of Lewy pathology in brain tissue is a key component of any post-mortem diagnosis of PD.[Halliday et al., 2014] A fundamental question yet to be resolved, however, is whether Lewy bodies are in themselves pathological (i.e., part of the disease) or a normal, protective response to the accumulation of misfolded α‑synuclein.[Shulman et al., 2011] Importantly, the presence of Lewy bodies in different regions of post-mortem brain tissue does not always correlate well with symptoms experienced by patients.[Halliday et al., 2014] This suggests that the symptoms of PD may be caused by other factors, such as the loss of dopaminergic neurons.[Halliday et al., 2014]
 

Halliday GM, Murphy K, Cartwright H. Pathology of Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Shulman JM, De Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol 2011; 6: 193–222.

Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009; 373 (9680): 2055–2066.

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α-synuclein
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The protein α-synuclein was first isolated from human brain tissue during the early 1990s.[Burré, 2015] Its role in PD only became apparent in 1997, when a mutation in the α-synuclein gene was discovered in groups affected by a rare, autosomal-dominant form of familial parkinsonism.[Polymeropoulos et al., 1997] Twenty years on, the precise function of α-synuclein is still unclear, but it appears to interact with and affect various proteins involved with vesicle formation in synapses (the physiological interfaces between nerve cells).[Burré, 2015; Halliday et al., 2014]

A key feature of PD is the aggregation – or clumping together – of misfolded α-synuclein into small filaments called ‘fibrils’.[Ropper et al., 2014] This aggregation continues until Lewy bodies are formed, which can ultimately lead to the destruction of the nerve cell.[Ropper et al., 2014]

The accumulation of α-synuclein in the development of PD means that the condition is often referred to as one of the ‘synucleinopathies’, along with several other neurodegenerative disorders (mainly dementia with Lewy bodies, and multiple system atrophy).[Burré, 2015] It is hoped that, by limiting the accumulation of α‑synuclein, these disorders can be prevented from developing in the first place.[Burré, 2015]

Burré J. The synaptic function of α-synuclein. J Parkinson Dis 2015; 5 (4): 699–713.

Halliday GM, Murphy K, Cartwright H. Pathology of Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276 (5321): 2045–2047.

Ropper AH, Samuels MA, Klein JP. Adams and Victor’s Principles of Neurology, 10th edition. New York: McGraw-Hill Education, 2014.

Lee VM, Trojanowski JQ. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 2006; 52 (1): 33–38. 

Dehay et al. Lancet Neurol 2015;14(8):855–866.

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Dopaminergic cell loss in Parkinson’s disease
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The overall level of atrophy of brain tissue does not seem to differ between patients with PD and age-matched controls.[Halliday et al., 2014] However, by the time a patient with PD develops motor symptoms, they will have suffered a moderate-to-severe loss of neuromelanin-pigmented, dopamine-producing neurons in the substantia nigra, which causes a severe depletion of dopamine in the striatum.[Halliday et al., 2014; Schulman et al., 2011] The loss of dark pigmentation in the substantia nigra is easily visible in the pale, post-mortem brain tissue of affected individuals (see slide).[Halliday et al., 2014]

 

Halliday GM, Murphy K, Cartwright H. Pathology of Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Shulman JM, de Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol 2011; 6: 193–222.

Michel PP, Hirsch EC, Hunot S. Understanding dopaminergic cell death pathways in Parkinson disease. Neuron 2016; 90 (4): 675–691.

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Braak staging of Parkinson’s disease
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At a physiological level, PD is characterised by the loss of neurons in specific regions of the brain and a spreading of Lewy pathology.[Halliday et al., 2014] However, these do not necessarily always go together; many regions with a concentration of Lewy pathology show only mild neuronal loss.[Halliday et al., 2014]
The widely-used scheme proposed by Braak and colleagues categorises PD into discrete stages of clinical progression.[Braak et al., 2004; Halliday et al., 2014] The first two stages involve early α‑synuclein deposition associated with the appearance of non-motor symptoms, such as olfactory (smell) and autonomic (vital) dysfunction.[Halliday et al., 2014] As the disease progresses, other aspects of brain function may become impaired, causing sleep dysregulation and/or depression in some individuals.[Halliday et al., 2014] 

Stage 4 is typically the point at which clinical diagnosis occurs, since this stage involves the onset of motor symptoms, such as resting tremor and bradykinesia.[Halliday et al., 2014] Stage 5 is characterised by poor balance and an increased susceptibility to falls, as well as the onset of cognitive impairment.[Halliday et al., 2014] By Stage 6, the patient is likely to be significantly physically disabled and cognitive decline may well have progressed to PD dementia.[Braak et al., 2004; Halliday et al., 2014]
The Braak staging scheme is a useful concept to distinguish between the different phases of PD. [Braak et al., 2004] However, in reality, patients vary considerably in the extent to which they conform to this model.[Halliday et al., 2014] In one study, less than half of all patients with PD whose brains were examined post-mortem showed a close fit to the Braak staging scheme.[Parkkinen et al., 2008] Another study found no pathology in the lower brainstem of some individuals (normally affected in Stage 1), even though it was clearly evident in higher regions.[Kalaitzakis et al., 2008] Together, these studies clearly demonstrate that, beneath the over-arching diagnosis of ‘idiopathic PD’, there exists a wide variety of different disease processes, each of which manifests with the clinical and physiological features of PD.[Halliday et al., 2014] 
 

Braak H, Ghebremedhin E, Rüb U, et al. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004; 318 (1): 121–134.

Halliday GM, Murphy K, Cartwright H. Pathology of Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease: a critical analysis of α-synuclein staging. Neuropathol Appl Neurobiol 2008; 34 (3): 284–295.

Parkkinen L, Pirttilä T, Alafuzoff I. Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance. Acta Neuropathol 2008; 115 (4): 399–407. 

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Distribution of α-synuclein pathology in Parkinson’s disease
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The Lewy pathology and aggregated α-synuclein proteins associated with PD are not confined to the central nervous system (CNS); they can also be found in the peripheral nervous system at various sites around the body, such as the skin, gastrointestinal tract, and salivary glands.[Tolosa & Vilas, 2015] The cause of these α-synuclein deposits is still unknown, as is the extent to which they reflect damage or loss of function in these areas.[Fasano et al., 2015; Tolosa & Vilas, 2015]
The relatively recent discovery of peripheral α-synuclein pathology could have profound consequences for the development of a useful biomarker of PD – one that could be measured during the pre-clinical or prodromal stages of the disease.[Tolosa & Vilas, 2015] Peripheral α-synuclein (i.e., that found outside the CNS) is easier to sample (in a skin or gut biopsy) than brain tissue.[Tolosa & Vilas, 2015] If viable, such a biomarker would not only be able to detect PD early, but it could also be used to distinguish the disease from similar forms of parkinsonism, such as multiple system atrophy.[Tolosa & Vilas, 2015; Wood, 2016] At present, however, researchers have yet to agree on a biopsy procedure that yields the most reliable diagnosis.[Tolosa & Vilas, 2015] 
 
 

Fasano A, Visanji NP, Liu LW, et al. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2015; 14 (6): 625–639. 

Tolosa E, Vilas D. Peripheral synuclein tissue markers: a step closer to Parkinson’s disease diagnosis. Brain 2015; 138 (8): 2120–2122.

Wood H. Parkinson disease: peripheral α-synuclein deposits – prodromal markers for Parkinson disease? Nat Rev Neurol 2016; 12 (5): 249.

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The gastrointestinal system and Parkinson’s disease
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Neurons found in the enteric (gut) nervous system (ENS) require dopamine.[Rao & Gershon, 2016] Without dopamine, these neurons cannot properly control gastrointestinal motility.[Rao & Gershon, 2016] Animal studies have suggested that the ENS may be vulnerable to degeneration during PD, and the finding of Lewy pathology in gut biopsy samples taken from patients with PD supports this.[Rao & Gershon, 2016] It may, therefore, be useful to measure levels of α-synuclein in the gut as a method of potentially diagnosing PD during its early stages.[Rao & Gershon, 2016] 

A gut-derived biomarker may be particularly valuable if, as some studies have suggested, PD develops first in the ENS and then moves up into the brainstem via nerve fibres.[Rao & Gershon, 2016] Experimental data using rodents have recently demonstrated (as a proof of concept) that the application of a toxin to the gastrointestinal system can lead to neurodegeneration in the central nervous system, including the brain.[Rao & Gershon, 2016] This ‘gut–brain’ hypothesis is further supported by epidemiological data that indicate a reduced risk of PD in individuals who had undergone truncal vagotomy, an operation that severs the vagus nerve connecting the ENS to the brain.[Svensson et al., 2015]

Rao M, Gershon MD. The bowel and beyond: the enteric nervous system in neurological disorders. Nat Rev Gastroenterol Hepatol 2016; 13 (9): 517–528.

Svensson E, Horváth-Puhó E, Thomsen RW, et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 2015; 78 (4): 522–529. 

Lema Tomé CM, Tyson T, Rey NL, et al. Inflammation and α-synuclein’s prion-like behavior in Parkinson’s disease – is there a link? Mol Neurobiol 2013; 47 (2): 561–574.

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α-synuclein and the ‘prion hypothesis’ of PD
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Aggregation of misfolded proteins
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According to the staging scheme of Braak and colleagues, the accumulation of aggregated α-synuclein that forms Lewy pathology is first seen in the lower parts of the brainstem during early PD, and then spreads over time in a relatively predictable way through different regions of the brain.[Braak et al., 2004] This phenomenon has been observed clearly in the brain tissue of deceased patients with PD, yet the mechanisms by which this spreading occurs have been difficult to ascertain.[Hauser, 2015] However, during the last decade, a growing amount of evidence has suggested that the α-synuclein proteins themselves may be responsible for the transmission of PD pathology from one area of the brain to another.[Stopschinski & Diamond, 2017] This is known as the ‘prion model’ of disease transmission.[Stopschinski & Diamond, 2017]

Braak H, Ghebremedhin E, Rüb U, et al. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004; 318 (1): 121–134.

Hauser RA. α-Synuclein in Parkinson’s disease: getting to the core of the matter. Lancet Neurol 2015; 14 (8): 785–786.

Stopschinski BE, Diamond MI. The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurol 2017; 16 (4): 323–332.

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What are ‘prions’?
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Prions are infectious and self-replicating protein entities, often involved in brain disorders.[Beisel & Morens, 2004; Brundin et al., 2016] Well-known examples of prion disease include bovine spongiform encephalopathy (BSE), also known as ‘mad cow disease’, and variant Creutzfeldt-Jakob disease (vCJD), a rare but fatal form of BSE transmitted to humans, which led to over 100 deaths in the UK between 1995–2003.[Beisel & Morens, 2004]

Because they are misfolded proteins, prions can form aggregates within cells.[Collinge & Clarke, 2007] It is now increasingly clear that misfolded proteins implicated in neurodegenerative disorders, such as α-synuclein in PD and β-amyloid in Alzheimer’s disease, may self-propagate in a prion-like manner.[Brundin et al., 2016; Collinge & Clarke, 2007] As such, researchers are becoming increasingly interested in the ‘prion model’ of neurodegenerative disorders.[Collinge & Clarke, 2007]
 

Beisel CE, Morens DM. Variant Creutzfeldt-Jakob disease and the acquired and transmissible spongiform encephalopathies. Clin Infect Dis 2004; 38 (5): 697–704.

Brundin P, Ma J, Kordower JH. How strong is the evidence that Parkinson’s disease is a prion disorder? Curr Opin Neurol 2016; 29 (4): 459–466.

Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science 2007; 318 (5852): 930–936.

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How strong is the evidence that Parkinson’s disease is a prion disease?
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In the 1990s, a small cohort of patients with PD received striatal transplants of foetal dopaminergic neurons in an attempt to compensate for lost capacity in the substantia nigra.[Freed et al., 2001; Kordower et al., 2008] The brain of one of these patients was examined after her death 14 years later.[Freed et al., 2001; Kordower et al., 2008] During the examination, it was observed that some of the grafted neurons in the patient’s brain tissue contained Lewy body-like inclusions that stained positively for α-synuclein, indicating its presence in the tissue.[Kordower et al., 2008] Although the patient had responded well to dopaminergic therapy for several years after her transplant, her symptoms had worsened again over time, which suggests that the striatal transplants had deteriorated due to α-synuclein-related pathology.[Kordower et al., 2008] This finding was subsequently confirmed in several similar clinical cases and replicated in animal models, including an experiment in which α-synuclein fibrils were injected into the olfactory bulb of mouse brains.[Stopschinski & Diamond, 2017; Rey et al., 2016] These fibrils ‘recruited’ normal α-synuclein to become insoluble aggregates, which then spread into other areas of the brain, causing loss of olfactory function.[Rey et al., 2016]

Overall, the evidence seems to strongly support the idea that PD pathology spreads through the nervous system by means of a prion-like, pathological propagation of aggregated α-synuclein.[Stopschinski & Diamond, 2017]
 

Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001; 344 (10): 710–719.

Kordower JH, Chu Y, Hauser RA, et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 2008; 14 (5): 504–506. 

Rey NL, Steiner JA, Maroof N, et al. Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J Exp Med 2016; 213 (9): 1759–1778. 

Stopschinski BE, Diamond MI. The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurol 2017; 16 (4): 323–332.

Brundin P, Ma J, Kordower JH. How strong is the evidence that Parkinson’s disease is a prion disorder? Curr Opin Neurol 2016; 29 (4): 459–466.

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Prions and dementia in Parkinson’s disease
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In general, the Lewy body pathology in the cerebral cortex is more extensive and severe in patients with PD-dementia than in those without dementia.[Irwin et al., 2013] Poorer performance on several measures of cognitive function is strongly correlated with increased amounts of α-synuclein in cortical regions of the brain.[Irwin et al., 2013] However, this may not always be the case; a minority of patients with PD-dementia have been found to have minimal cortical Lewy pathology at autopsy, indicating that this feature may not be an essential component of the disorder.[Irwin et al., 2013] However, it may be that, in these cases at least, dementia was caused by Lewy pathology in sub-cortical regions that also affect cognitive function, or perhaps by the presence of other neurological disease processes.[Irwin et al., 2013] 

There appears to be a certain degree of crossover between PD and other neurological disorders associated with ageing, such as Alzheimer’s disease.[Irwin et al., 2013] For example, the accumulation of α‑synuclein pathology is not just confined to patients with PD symptoms; it is also found in up to 50% of patients with Alzheimer’s disease (although it tends to be restricted to the amygdala).[Irwin et al., 2013] Similarly, the β-amyloid plaques and tau tangles associated with Alzheimer’s disease are also often found in patients with PD.[Irwin et al., 2013] In such cases, these different forms of protein aggregation may exert a synergistic effect to increase the level of cognitive dysfunction experienced by the patient.[Irwin et al., 2013]
 

Irwin DJ, Lee VMY, Trojanowski JQ. Parkinson’s disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci 2013; 14 (9): 626–636. 

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Risk factors for Parkinson’s disease
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The aetiology of Parkinson’s disease
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The cause(s) of PD remain to be elucidated; multiple pathogenic mechanisms have been proposed, ranging from oxidative stress to protein aggregation, and mitochondrial genetic defects.[Morgan & Sethi, 2006] The slide shows how the range of potential risks and mechanisms may all interact to lead to the development of pathology.

 

Morgan JC, Sethi KD. Emerging drugs for Parkinson’s disease. Expert Opin Emerg Drugs 2006; 11 (3): 403–417.

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Environmental risk factors for Parkinson’s disease
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Factors associated with PD
Researchers have found several environmental (non-genetic) factors that appear to be associated with PD.[Campdelacreu, 2014] Some of these may have a causal relationship with PD, involved either as disease-causing or protective elements.[Bellou et al., 2016; Campdelacreu, 2014] Potential disease-causing risk factors include pesticides and high dietary iron intake, whereas potentially protective risk factors include physical activity and tobacco use.[Bellou et al., 2016; Campdelacreu, 2014] Other risk factors, such as constipation and anxiety/depression, are commonly associated with the development of PD, but are more likely to be a consequence, rather than a cause, of the disease.[Bellou et al., 2016]

Tobacco use
Tobacco use, whether through smoking or ingesting, has been consistently associated with a reduced risk of PD.[Yang et al., 2016] A wide range of evidence has indicated that nicotine is likely to be the protective element in tobacco, yet human clinical trials of nicotine therapy have thus far produced inconsistent results.[Quik et al., 2008; Thiriez et al., 2011] 

Physical activity
Higher levels of physical activity have been consistently associated with a lower risk of PD.[Bellou et al., 2016] This may be due to the effect of physical activity on uric acid levels in blood, since higher levels of uric acid are considered to reduce the risk of PD.[Bellou et al., 2016] An alternative interpretation, however, is that individuals with preclinical PD have poorer neurological function, which causes them to be less physically active.[Bellou et al., 2016] In such cases, reduced physical activity would actually be a consequence of PD, rather than protecting against it.[Bellou et al., 2016] Higher quality evidence is needed to clearly establish a protective effect of physical activity on PD risk.[Bellou et al., 2016]
 

Bellou V, Belbasis L, Tzoulaki I, et al. Environmental risk factors and Parkinson’s disease: an umbrella review of meta-analyses. Parkinsonism Relat Disord 2016; 23: 1–9.

Campdelacreu J. Parkinson’s disease and Alzheimer disease: environmental risk factors. Neurologia 2014; 29 (9): 541–549. 

Quik M, O’Leary K, Tanner CM. Nicotine and Parkinson’s disease: implications for therapy. Mov Disord 2008; 23 (12): 1641–1652.

Thiriez C, Villafane G, Grapin F, et al. Can nicotine be used medicinally in Parkinson’s disease? Expert Rev Clin Pharmacol 2011; 4 (4): 429–436.

Yang F, Pedersen NL, Ye W, et al. Moist smokeless tobacco (snus) use and risk of Parkinson’s disease. Int J Epidemiol 2017; 46 (3): 872–880.

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Susceptibility genes
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The figure in the slide is a graphical representation of genetic influences on the risk of developing PD.[Clarimón & Kulisevsky, 2013] The vertical Y-axis shows the strength of genetic effects, and the horizontal X-axis indicates the age at onset of disease, from juvenile to late onset.[Clarimón & Kulisevsky, 2013]

  • The red circles represent autosomal-recessive genes, which require two copies of the abnormal gene (i.e., one from each parent).[Clarimón & Kulisevsky, 2013] 
  • The orange circles represent autosomal-dominant genes, which require only one copy of the abnormal gene (i.e., one from either parent).[Clarimón & Kulisevsky, 2013] 
  • The gold circles represent PD risk loci – i.e., positions on chromosomes associated with an increased susceptibility to PD.[Clarimón & Kulisevsky, 2013]
  • The relative size of each circle in the figure reflects the extent to which each genetic variant contributes to the prevalence of PD in a typical population.[Clarimón & Kulisevsky, 2013]

The figure clearly shows that genes with the greatest impact on individual PD risk tend to exert their influence earlier in life, and are mostly rare.[Clarimón & Kulisevsky, 2013; Schulte & Gasser, 2011] Mutations in the Parkin gene are the most common, known cause of early-onset PD (average age at onset is 32 years).[Schulte & Gasser, 2011] By contrast, less potent genes – i.e., those that merely increase susceptibility to PD, but do not necessarily lead to clinical disease – are generally associated with a much older age of onset, and make a greater overall contribution to PD in the general population.[Clarimón & Kulisevsky, 2013]

Clarimón J, Kulisevsky J. Parkinson’s disease: from genetics to clinical practice. Curr Genomics 2013; 14 (8): 560–567.

Schulte C, Gasser T. Genetic basis of Parkinson’s disease: inheritance, penetrance, and expression. Appl Clin Genet 2011; 4: 67–80.

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Genetic risk factors for Parkinson’s disease
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The slide shows various genetic ‘loci’ (i.e., locations on specific chromosomes) that have been implicated in the development of PD.

Simple inheritance modes
Several genes have been identified as increasing the risk of PD.[Shulman et al., 2011] A small proportion (<10%) of PD cases appear to arise through simple modes of inheritance, whereby a single gene is passed on by one or both parents that results in development of PD.[Schulte & Gasser, 2011] These types of gene variant tend to be rare but have major effects on health.[Shulman et al., 2011] For example, rare mutations in the SNCA gene on chromosome 4q21 (see slide), which codes for α-synuclein, can cause familial, early-onset PD, frequently with a rapid disease progression and early dementia.[Shulman et al., 2011]

Complex inheritance patterns
Much of the genetic risk in a population is caused by the complex interaction and accumulation of multiple ‘susceptibility’ genetic variants.[Escott-Price et al., 2015] Although some of these variants may contribute only a small amount of risk when looked at in isolation, an individual with multiple susceptibility variants is likely to have a higher cumulative risk of PD, particularly when combined with environmental risk factors or old age.[Shulman et al., 2011]

Influence of gene identification
Until fairly recently, most genetic studies of PD relied on ‘linkage’ analyses, which track the segregation of chromosomal regions in families where multiple members have been affected by the disease.[Shulman et al., 2011] However, this has now been largely superseded by genome-wide association studies (GWAS), which seek out genetic variation associated with PD in the wider population.[Shulman et al., 2011] GWAS can be particularly useful for identifying highly-prevalent variations in genes associated with relatively weak effects on PD risk.[Shulman et al., 2011] For example, one well-known variant at the SNCA locus is associated with a fairly modest increase in PD risk, yet is present in nearly half of all people of white origin.[Shulman et al., 2011; Simón-Sánchez et al., 2009]
 

Escott-Price V, Nalls MA, Morris HR, et al.; International Parkinson’s Disease Genomics Consortium. Polygenic risk of Parkinson disease is correlated with disease age at onset. Ann Neurol 2015; 77 (4): 582–591. 

Shulman JM, de Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol 2011; 6: 193–222.

Schulte C, Gasser T. Genetic basis of Parkinson’s disease: inheritance, penetrance, and expression. Appl Clin Genet 2011; 4: 67–80.

Simón-Sánchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009; 41 (12): 1308–1312.

Scholz SW, Mhyre T, Ressom H, et al. Genomics and bioinformatics of Parkinson’s disease. Cold Spring Harb Perspect Med 2012; 2 (7): a009449.

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Monogenic causes of Parkinson’s disease
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References

The first genetic mutation known to cause PD was discovered in the SNCA gene in 1997.[Polymeropoulos et al., 1997] It was a point mutation (A53T) that occurred in a few Italian and Greek families, each of which had a history of early-onset PD.[Polymeropoulos et al., 1997] Since then, several other gene mutations and multiplications have been found to cause PD, and many others have been associated with parkinsonian symptoms.[Puschmann, 2013]

Approximately 10% of patients with PD have a first-degree relative with the disease but, even within this sub-group, single-gene mutations constitute only a small proportion of cases.[Puschmann, 2013] In general, the likelihood of finding a known pathogenic mutation in a patient with parkinsonism remains low, but can vary with a patient’s age at onset, family history, origin, and clinical presentation.[Puschmann, 2013]

Some healthcare systems now offer genetic testing for patients, particularly those with early onset of PD symptoms, since several well-established genetic mutations (e.g., in Parkin, PINK1, DJ-1) are associated with this type of disease presentation.[Puschmann, 2013] Genetic tests can help to assess the risk of passing on a PD-related gene to one’s children and can provide useful information with regard to prognosis and therapeutic decisions.[Berardelli et al., 2013; Puschmann, 2013] Patients undergoing such tests should be provided with genetic counselling at every stage – before, during, and after receiving the results.[Puschmann, 2013]

Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES/ENS recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol 2013; 20 (1): 16–34.

Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276 (5321): 2045–2047.

Puschmann A. Monogenic Parkinson’s disease and parkinsonism: clinical phenotypes and frequencies of known mutations. Parkinsonism Relat Disord 2013; 19 (4): 407–415.

Halliday GM, Murphy K, Cartwright H. Pathology of Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014. 

Schapira AHV, Tolosa E. Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nat Rev Neurol 2010; 6 (6): 309–317.

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Genetic factors in Parkinson’s disease varying by ethnicity
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Many genome-wide analyses of the genetics of PD have been undertaken to date. However, these analyses are typically conducted using patients from the same ethnic group, for example patients of European ancestry, or patients of East Asian ancestry.[Simón-Sánchez et al., 2009; Foo et al., 2017] Furthermore, the methodology of a genome-wide analysis will vary depending on the ethnic group being studied, because of differences within the genetics of individuals from different ancestry (for example, there is more genetic variation within individuals of African origin than within some other groups, and so the genome-wide study will be tailored to this).[Foo et al., 2012] There is a danger, therefore, that the results of a genetic analysis conducted in patients of a particular ethnic background cannot be applied to patients of different ethnicity.[Foo et al., 2012] 

Foo JN, Liu JJ, Tan EK. Whole-genome and whole-exome sequencing in neurological diseases. Nat Rev Neurol 2012; 8: 508–517.

Foo JN, Tan LC, Irwan ID, et al. Genome-wide association study of Parkinson’s disease in East Asians. Hum Mol Genetics 2017; 26 (1): 226–232.

Simón-Sánchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009; 41 (12): 1308–1312.
 

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Common pathways underlying PD pathogenesis
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The pathogenesis of Parkinson’s disease
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References

The physiological development of PD is highly complex, but recent advances in genetic epidemiology have shown that certain key processes involved in cellular metabolism may play important roles.[Schulte & Gasser, 2011] Of particular importance are the processes involved in degrading misfolded proteins, such as α-synuclein.[Schulte & Gasser, 2011] Degradation is normally effected by lysosomes and proteasomes, which break down old or abnormal proteins.[Schulte & Gasser, 2011] However, in PD these processes can become impaired, leading to an accumulation of fibrillar, misfolded α-synuclein in the cell.[Schulte & Gasser, 2011]

Schulte C, Gasser T. Genetic basis of Parkinson’s disease: inheritance, penetrance, and expression. Appl Clin Genet 2011; 4: 67–80.

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The importance of mitochondria in Parkinson’s disease
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Mitochondria are known as the ‘power plants of the cell’. They use metabolic fuels such as glucose to produce the high-energy molecule, adenosine triphosphate (ATP), which drives many important physiological processes.

A toxic by-product of normal mitochondrial function is the generation of free radicals, which in sufficient amounts can cause oxidative stress.[Moore et al., 2005] Maintenance and response to this oxidative stress are regulated by the genes DJ-1, PINK1, Parkin, and UCH-L1, all of which have mutations associated with PD.[Schapira, 2008] Taken together, the evidence from these genes strongly suggests that mitochondrial function plays an important role in the pathology of PD.[Schapira, 2008]
 

Moore DJ, West AB, Dawson VL, Dawson TM. Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 2005; 28: 57–87.

Schapira AHV. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol 2008; 7 (1): 97–109.

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Mitochondrial dysfunction plays a key role in Parkinson’s disease
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References

A large body of evidence suggests that mitochondrial dysfunction is a common pathological mechanism in several neurodegenerative diseases, including PD.[Chaturvedi & Beal, 2008]

Mitochondrial dysfunction has been shown to lead to the destruction of neurons as a result of oxidative stress, mitochondrial DNA (deoxyribonucleic acid) deletions, pathological mutations, altered mitochondrial morphology, and interaction with pathogenic proteins, such as α-synuclein.[Chaturvedi & Beal, 2008]

Over-expression of α-synuclein has been shown to impair mitochondrial function and increase vulnerability to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a prodrug of the neurotoxin MPP+ (1-methyl-4-phenylpyridinium) that is used in animal models to mimic PD.[Chaturvedi & Beal, 2008] By contrast, the absence of α-synuclein in mice confers resistance to respiratory chain inhibitors such as MPTP, 3-nitropropionic acid and malonate, which suggests that mitochondria play a key role in α-synuclein mediated toxicity during PD.[Chaturvedi & Beal, 2008]

 

Chaturvedi RK, Beal MF. Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 2008; 1147: 395–412.

Trimmer PA, Borland MK, Keeney PM, et al. Parkinson’s disease transgenic mitochondrial cybrids generate Lewy inclusion bodies. J Neurochem 2004; 88 (4): 800–812.

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Pathways linking genetic and idiopathic Parkinson’s disease – SNCA
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Linkage analysis studies have identified several SNCA mutations associated with familial, late-onset PD.[Trinh & Farrer, 2013] These mutations include dominantly inherited substitutions, such as Ala30Pro and Ala53Thr, as well as multiplication events – typically duplications and triplications.[Trinh & Farrer, 2013]

Triplication of SNCA leads to greater expression of α-synuclein, as compared with duplication, as well as an earlier onset and faster progression of PD, which suggests that the severity of PD may be dependent upon α-synuclein levels.[Martin et al., 2011; Trinh & Farrer, 2013] This has led to the widely held hypothesis that enhanced activity of α-synuclein underlies pathogenesis in PD.[Martin et al., 2011; Trinh & Farrer, 2013] Indeed, since expression of SNCA increases with age in brains unaffected by PD, some investigators have proposed that PD is actually an accelerated variant of the normal process of ageing, with the inadequate degradation of overexpressed α-synuclein playing a central role.[Mullin & Schapira, 2013]

Evidence suggests that the mechanisms by which an increased expression of SNCA leads to PD may involve direct mitochondrial toxicity.[Mullin & Schapira, 2013] Although the precise mechanisms by which this occurs are still unclear, several studies have demonstrated that SNCA interferes with the processes of mitophagy (the selective degradation of mitochondria) and mitochondrial fusion.[Mullin & Schapira, 2013] Furthermore, oxidative stress resulting from mitochondrial dysfunction may lead to the aggregation of α-synuclein, which is a key step in the degeneration of dopaminergic neurons.[Martin et al., 2011]
 

Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet 2011; 12: 301–325.

Mullin S, Schapira A. α-Synuclein and mitochondrial dysfunction in Parkinson’s disease. Mol Neurobiol 2013; 47 (2): 587–597.

Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol 2013; 9 (8): 445–454.

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Pathways linking genetic and idiopathic Parkinson’s disease – LRRK2
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LRRK2 is a large and complex protein with multiple domains and functions, such as GTPase and kinase activity, and protein binding.[Martin et al., 2011; Martin et al., 2014]
LRRK2 mutations are the most common cause of genetic PD.[Martin et al., 2014] Genome-wide association studies (GWAS) have identified several LRRK2 polymorphisms associated with an increased risk of PD.[Esteves et al., 2014] In the presence of certain mutations, such as Asn1437His or Gly2019Ser, LRRK2 may cause autosomal-dominant PD.[Trinh & Farrer, 2013] However, in some people, LRRK2 appears to act as a ‘susceptibility’ gene, increasing the risk of PD.[Esteves et al., 2014]

LRRK2 plays a role in several cellular activities, including maintenance of the cytoskeleton, and various signalling cascades.[Esteves et al., 2014] It is involved in microtubular and mitochondrial dynamics, allowing efficient intracellular trafficking within the axon.[Esteves & Cardoso, 2015] Mutations in LRRK2 are thought to disrupt these functions.[Esteves & Cardoso, 2015] 

One of the mechanisms by which LRRK2 plays a role in the pathogenesis of PD may be through its interactions with α-synuclein.[Daher et al., 2014] Rats deficient in LRRK2 expression are protected from the degeneration of dopaminergic neurons caused by overexpression of α-synuclein.[Daher et al., 2014] Another mechanism may involve the promotion of neuroinflammation, a process thought to play a key role in the pathogenesis of PD.[Daher et al., 2014] 

Daher JP, Volpicelli-Daley LA, Blackburn JP, et al. Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc Natl Acad Sci USA 2014; 111 (25): 9289–9294.

Esteves AR, Swerdlow RH, Cardoso SM. LRRK2, a puzzling protein: insights into Parkinson’s disease pathogenesis. Exp Neurol 2014; 261: 206–216.

Esteves AR, Cardoso SM. LRRK2 a pivotal player in mitochondrial dynamics and lysosomal clustering: highlights to sporadic Parkinson’s disease. Ther Targets Neurol Dis 2015; 2: e629.

Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet 2011; 12: 301–325.

Martin I, Kim JW, Dawson VL, Dawson TM. LRRK2 pathobiology in Parkinson’s disease. J Neurochem 2014; 131 (5): 554–565.

Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol 2013; 9 (8): 445–454.

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Pathways linking genetic and idiopathic Parkinson’s disease – Parkin
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References

Parkin is a ubiquitin ligase found primarily in the cytoplasm of the cell.[Martin et al., 2011] It ‘tags’ proteins to facilitate their proteasomal degradation.[Martin et al., 2011; Trinh & Farrer, 2013] Loss-of-function mutations in Parkin are associated with familial PD.[Martin et al., 2011]

Both parkin and PINK1 (a related protein) function in a mitochondrial quality control pathway that may become defective in cases of PD.[Martin et al., 2011] In a healthy individual, PINK1 detects dysfunctional mitochondria, and then signals their removal by parkin-mediated mitophagy.[Castillo-Quan, 2011] Loss-of-function mutations in either PINK1 or Parkin may therefore allow the continued survival of damaged mitochondria.[Castillo-Quan, 2011]

In addition to their effects on mitophagy, loss-of-function Parkin mutations lead to upregulated expression of PARIS, a protein that would normally repress PGC‑1α.[Castillo-Quan, 2011] Since one of the key roles of PGC-1α is to promote mitochondrial biogenesis, the higher levels of PARIS inhibit the production of new mitochondria.[Castillo-Quan, 2011] Parkin mutations thus via two mechanisms exert an effect on mitochondrial health within the cell, leading to increased levels of reactive oxygen species (owing to mitochondrial dysfunction) and neuronal cell death.[Castillo-Quan, 2011]
 

Castillo-Quan JI. Parkin’ control: regulation of PGC-1α through PARIS in Parkinson’s disease. Dis Model Mech 2011; 4 (4): 427–429.

Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet 2011; 12: 301–325.

Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol 2013; 9 (8): 445–454.

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The role of neuroinflammation in Parkinson’s disease
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PD is strongly associated with older age, and older age is itself associated with increased levels of chronic inflammation.[Rocha et al., 2015] Neuroinflammation appears to be central to the disease process of PD.[Rocha et al., 2015]

Under normal conditions, acute insults to the central nervous system (CNS) trigger microglial activation, causing microglia to change shape, increase their rate of proliferation, and produce inflammatory mediators that promote the recruitment of peripheral leukocytes to the CNS.[Rocha et al., 2015] When properly regulated, this process is considered to be beneficial because it allows potentially hazardous cell debris to be cleared.[Rocha et al., 2015] However, an excessive inflammatory response may lead to neurodegeneration.[Gao & Hong, 2008] In such cases, inflammatory mediators may act directly upon healthy neuronal tissue, causing it to be damaged, and ultimately leading to cell death.[Rocha et al., 2015] The resulting cellular debris in turn activates further inflammatory processes, leading to a vicious cycle of inflammation and neuronal death.[Rocha et al., 2015]

Neuronal tissue has a limited ability to regenerate, and the CNS is therefore highly vulnerable to uncontrolled immune and inflammatory processes.[Rocha et al., 2015] The dopaminergic neurons of the substantia nigra are particularly vulnerable to microglial-mediated neurotoxicity.[Rocha et al., 2015] Chronic neuroinflammation may therefore be the background in which the progressive degeneration of dopaminergic neurons occurs.[Tansey et al., 2007]

Gao HM, Hong JS. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 2008; 29 (8): 357–365.

Rocha NP, de Miranda AS, Teixeira AL. Insights into neuroinflammation in Parkinson’s disease: from biomarkers to anti-inflammatory based therapies. Biomed Res Int 2015; 2015: 628192.

Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 2007; 208 (1): 1–25.

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Gaucher disease – glucocerebrosidase
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Gaucher disease is a rare, autosomal-recessive disease that involves a wide range of organ systems, including the liver, spleen, and bone.[Migdalska-Richards & Schapira, 2016] It is caused by mutations in the GBA1 gene, which codes for the enzyme glucocerebrosidase.[Schapira, 2015] This enzyme is required for the normal function of lysosomes, one of the cellular components that degrade unwanted materials within the cell.[Schapira, 2015]

Mutations in the GBA1 gene are thought to constitute the most important predisposing risk factor – numerically at least – for developing PD.[Migdalska-Richards & Schapira, 2016] Both homozygous GBA1 (two copies of the gene variant required; one from each parent) and heterozygous GBA1 (one copy required from either parent) confer a 20‐ to 30‐fold increased risk for PD, and it is estimated that approximately 5–10% of patients with PD have a GBA1 mutation.[Migdalska-Richards & Schapira, 2016] Mutant glucocerebrosidase is thought to increase levels of α-synuclein.[Schapira, 2015]

The effect of these findings has been to demonstrate that defects in the synthesis of glucocerebrosidase, and thus the protein-recycling function of lysosomes in general, is likely to play a key role in the pathogenesis of PD.[Schapira, 2015]

Migdalska-Richards A, Schapira AH. The relationship between glucocerebrosidase mutations and Parkinson disease. J Neurochem 2016; 139 Suppl 1: 77–90.

Schapira AH. Glucocerebrosidase and Parkinson disease: recent advances. Mol Cell Neurosci 2015; 66 (Pt A): 37–42.

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The clinical features of GBA1-positive Parkinson’s disease
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Individuals with PD who carry GBA1 gene mutations tend to differ from typical cases of idiopathic PD.[Sidransky et al., 2009] They present with motor symptoms on average four years earlier and often have a family history of PD.[Sidransky et al., 2009] Individuals with GBA1-PD tend to have a significantly lower incidence of bradykinesia, muscular rigidity and resting tremor, and a greater incidence of impaired cognitive function.[Sidransky et al., 2009]

Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 2009; 361 (17): 1651–1661. 
 

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Designing treatments based on the pathogenesis model; where to target
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Novel therapeutic strategies for Parkinson’s disease
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References

It is becoming increasingly apparent that the clinical progression of PD relies upon the cell-to-cell propagation of a-synuclein aggregates.[Brundin et al., 2015] This, therefore, presents researchers with potentially powerful therapeutic targets that might inhibit this propagation process.[Brundin et al., 2015]

One option would be to reduce levels of α-synuclein in the extracellular space (mostly in the space between neurons).[Brundin et al., 2015] Therapeutic agents could inhibit the release of α-synuclein, or its uptake by neurons, which would prevent the pathological spread of α-synuclein to other neurons.[Brundin et al., 2015] Antibodies that bind specifically to misfolded α-synuclein have shown considerable promise in this regard although, so far, only in animal models of PD.[Brundin et al., 2015; Hasegawa et al., 2017] 

Another option would be to reduce the extent to which α-synuclein proteins join together into fibrils.[Brundin et al., 2015] This is most likely to be achieved by small molecule compounds that can cross the blood–brain barrier, enter into affected nerve cells, and then specifically bind to the misfolded α-synuclein.[Hasegawa et al., 2017] In this way, these molecules should be able to prevent the proteins from multiplying and spreading.[Hasegawa et al., 2017] A bolder approach might be to prevent further α-synuclein aggregation by ‘knocking-out’ the SNCA gene, or at least reducing its expression, through some form of gene therapy.[Hasegawa et al., 2017] However, research in this area is still restricted to animal models, and the potential effects of such a treatment on human brain function remain extremely unclear.[Hasegawa et al., 2017]
In addition to potential therapies targeting alpha-synuclein, there are other targets that are being investigated based on the known or hypothesised aetiology of PD.[Harikrishna Reddy et al., 2014]

Brundin P, Atkin G, Lamberts JT. Basic science breaks through: new therapeutic advances in Parkinson’s disease. Mov Disord 2015; 30 (11): 1521–1527. 

Harikrishna Reddy D, Misra S, Medhi B. Advances in drug development for Parkinson’s disease: present status. Pharmacology 2014; 93 (5–6): 260–271.

Hasegawa M, Nonaka T, Masuda-Suzukake M. Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders. Pharmacol Ther 2017; 172: 22–33.

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The future of Parkinson’s disease treatments
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Recent advances in the understanding of the physiological processes affected by PD have led to a wealth of potential new opportunities to treat the disease.[Kalia et al., 2015] Many of these, particularly immunotherapy, are still in the very early stages, but there are now clearer strategies and targets for which to aim.[Brundin et al., 2015]
It is now realised that many of the major neurodegenerative diseases associated with ageing – PD, Alzheimer’s disease, and others – are linked by similar underlying pathological processes, such as protein aggregation and prion-like propagation.[Brundin et al., 2016] This increased understanding has opened up new and exciting targets for tackling these diseases.

Brundin P, Atkin G, Lamberts JT. Basic science breaks through: new therapeutic advances in Parkinson’s disease. Mov Disord 2015; 30 (11): 1521–1527. 

Brundin P, Ma J, Kordower JH. How strong is the evidence that Parkinson’s disease is a prion disorder? Curr Opin Neurol 2016; 29 (4): 459–466.

Kalia LV, Kalia SK, Lang AE. Disease-modifying strategies for Parkinson’s disease. Mov Disord 2015; 30 (11): 1442–1450.
 

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