Parkinson's Disease (Pathogenesis and Its Management): An Overview

Kumar BNP¹, Naresh Korrapati^2*, Shabana Kouser Ali³and Shaik Mohammed Irshad²

¹Livestock Research Institute, College of Veterinary Science, SVVU, Hyderabad, India

²Department of Biotechnology, Sri Krishna Devaraya University, Anantapur, India

³Department of BioInformatics, VIT, Tamil Nadu, India

*Corresponding Author:

Naresh Korrapati
Department of Bio-Technology
Sri Krishna Devaraya University
College of Engineering and Technology
Sri Krishna Devaraya University, Anantapur
Andhra Pradesh, India
Tel: +91-9492654991
E-mail: korrapatinaresh991@ gmail.com

Received date: October 13, 2016; Accepted date: November 07, 2016; Published date: November 14, 2016

Citation: Kumar BNP, Korrapati N, Ali SK, Irshad SM (2016) Parkinson�s Disease (Pathogenesis and Its Management): An Overview. J Alzheimers Dis Parkinsonism 6: 284. doi: 10.4172/2161-0460.1000284

Copyright: © 2016 Kumar BNP, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Parkinson’s disease (PD) is an idiopathic neurodegenerative disorder which has its incidence mainly in elderly aged humans. Loss of dopaminergic neurons especially in the substantia nigra, presence of α-synuclein Lewy bodies, mitochondrial dysfunction are the main pathological implications that plays pivotal role in both sporadic and familial forms of the disease. As PD affects older adults mostly in economically developed countries and worldwide aging populations there is an urgent need to develop strategies for the health care of individuals with PD. Epidemiological studies help in better understanding of the risk factors for PD and also helps in management of the disease and effective planning of medical services. In this present review article current understanding of Pathophysiology, Risk factors of PD were presented and the latest therapeutic approaches were discussed.

Keywords

Parkinson’s disease; Neurodegenerative disease; Mitochondria

Introduction

According to World Health Organization Neurodegenerative diseases are the leading cause for death in the elderly, and it predicted that by 2040, neurodegenerative diseases will go to second place in overall cause for death after cardiovascular diseases [1]. Parkinson’s disease (PD) sometimes called “paralysis agitans,” was first recognised in early 1800’s by the physician after whom the disease is named. Parkinson’s disease which is an idiopathic degenerative disease of nervous system affects both non-motor and motor system. PD is a progressive chronic neurodegenerative disorder mostly affecting older persons but it can also occur in younger people. But, PD is highly uncommon in young people and its incidence is very less in people under 40 years of age. Men are at more risk than women, men are 1.5 times more likely to develop PD than women. This difference is slightly varied from based on their geographical location for example PD is seen more in people with an older age in Western populations than Eastern countries. However, further studies are required confirm the ethnic differences in PD risk.

Estimates suggest that PD is expected to rise at an accelerated rate over the next 20 years in the aged individuals and continues as an important health issue with significant economic drain due to its direct and indirect healthcare costs. The economic and psychological burden is proved to be highly significant in developed nations where the average lifespans of the people are continuously increasing due to medical advancements.

Therefore, there is an urgent need in developing effective treatments for PD through research in medical and pharmaceutical fields.

Pathophysiology

Aggregation of alpha synuclein (α-syn)

Investigating the role of the protein alpha synuclein (α-syn) in the pathophysiology of Parkinson’s disease (PD) has begun in 1997. For the first time scientists found that a missense mutation in α-syn gene causes familial PD [2]. In the same year other studies proved that α-syn as one of the main components of Lewy bodies [3], which is the important neuropathological feature of PD [4]. The aggregation of α-syn causes a spectrum of disorders termed as synucleinopathies and a hypothesis has been put forward that α-syn aggregation results in toxicity through a gain-of-function mechanism. But, some studies proved that the α-syn plays an import role in a diverse range of essential cellular processes such as response to cellular stress and the regulation of neurotransmission.

α-synuclein immunoreactive protein aggregation in some selectively vulnerable neuronal types is crucial for the onset of sporadic Parkinson’s disease. The initial misfolding and subsequent aggregation of α-syn occurs in the enteric nervous system and/or the olfactory bulb which are exposed to potentially hostile environment. Generally these inclusions occur in cell somata in the form of spherical Lewy bodies [5- 8], as thread-like Lewy neurites or elongated spindle-shaped. Whereas in axons and dendrites [9-12], these develop as pale bodies [13], which are granular or dot-like or sometimes in punctate shape aggregates [14,15].

Distribution pattern of α-syn aggregates in the nervous system of PD patients

Development of α-syn aggregates generally progresses caudorostrally through lower brainstem regions such as lower raphe nuclei, dorsal motor nucleus of the vagal nerve, magnocellular nuclei, locus coeruleus then into midbrain tegmental nuclei mainly in the region of dopaminergic neurons of the substantia nigra and noncortical centres of the forebrain such as amygdala, magnocellular nuclei of the hypothalamic tuberomammillary nucleus, basal forebrain, midline and intralaminar nuclei of the thalamus. Finally, it reaches to the cerebral cortex. [16-22].

Spreading of α-syn along axonal connectivity

Recent studies had proved that the brain regions and nerve cells that become sequentially involved in PD are anatomically interconnected, even over long distances, and the physical contacts between nerve cells and axonal transport are involved in PD pathogenesis [23-25]. Many studies have proved the retrograde axonal transport of α-syn from peripheral nervous system to the central nervous system (CNS) [26], However the connections between the enteric nervous systems (ENS) and CNS by the vagus nerve play major role in the progression of PD [27,28]. Recent large-scale epidemiologic analysis of vagotomies that were performed to treat peptic ulcers have showed the involvement of ENS in the PD [29].

Finally, we can conclude that the misfolded and aggregated α-synuclein seeds can spread trans-synaptically through multisynaptic pathways and can function in a strain-dependent manner as self-propagating pathogens in disease progression [30-54]. The PD related damage occurs mainly in the superordinate centres of the limbic, somatomotor and visceromotor systems.

Cortical atrophy

Cortical atrophy is also one of the primary clinical manifestations in patient with PD. Till now three subtypes of cortical atrophies were identified in non-demented Parkinson’s disease patients. They are frontal and occipital cortical atrophy especially in younger disease onset, parieto-temporal atrophy in worse cognitive performance and finally in patients without detectable cortical atrophy. These atrophy patterns help in identifying the prognosis of the disease.

Mitochondria Dysfuntion

Mitochondrial dysfunction is associated with PD. Dysfunction of mitochondria may be due to mutations in genomic DNA effecting Mitochondria or bioenergetic defects or Mitochondrial DNA mutations or Morphological and physiological changes affecting the dynamics of the mitochondria such as changes in fusion or fission, size and morphology, trafficking or transport, movement of mitochondria, transcription, and the presence of altered or misfolded proteins.

Mitochondrial respiration in PD

Mitochondrial respiration alterations are involved in PD. Some compounds like Rotenone, trichloroethylene etc., inhibit complex I of mitochondria reduces movement of mitochondria, increases generation of reactive oxygen species (ROS), resulting in dopaminergic neurodegeneration suggesting that mitochondrial dysfunction plays an important role in PD [55,56]. In the substantia nigra, in the skeletal muscles and platelets the activity of complex I is impaired in PD patients [55,57,58]. Recent studies have shown that post translationally modified α-synuclein with high affinity binds to translocase of outer membrane (TOM20) of mitochondria and inhibits the transport of proteins into the mitochondria. This abnormal α-synuclein-TOM20 interaction was observed in nigrostriatal dopaminergic neurons in the post-mortem of brains from PD patients [59].

Genetic mutations affecting mitochondria

Generally Parkinson’s disease is well-thought-out as a non-genetic disorder where about 15% of entities with PD have a first-degree relative having the disease and for remaining 5% of individuals it’s because of mutations in some specific genes. Mutations in certain genes affecting mitochondrial structure and function are known to play a key role in familial PD. DJ-1, α-synuclein, Parkin, LRRK2, NURR1, PTEN-induced kinase1 (PINK1), vacuolar protein sorting 35 (VPS35), UCHL-1 and HtrA2 have pathogenic mutations which directly or indirectly affect mitochondrial normal functions has been observed in familial PD [55,60,61]. Juvenile Parkinsonism is mainly caused by Parkin which is an autosomal recessive disorder. Parkin gene encodes an enzyme E3 which is called as ubiquitin protease ligase. By these it can be concluded that mutations in PINK1 and Parkin causes defects in the functioning of mitochondria and also mitophagy [62]. Transcriptional up-regulation of PARK2 gene in response to damage of mitochondria leads to the loss of vacuolar protein sorting 13C (VPS13C) function this leads to the early onset of autosomal-recessive Parkinsonism [63].

Recent studies have shown that heterozygous mutations in glucocerebrocidase (GCase) gene is also frequently found in patients with PD [64,65]. Mutations in Leucine-rich repeat kinase 2 gene has a major role in monogenic PD in several populations [66,67].

Lysosomal dysfunction

A number of different types of mutations in PARK-genes are associated with the mitophagy or autophagy–lysosome pathway [68,69]. Lysosomal p-type ATPase13A2/PARK13 [70], alpha-synuclein (PARK1, PARK4) are fully or partly degraded by lysosomes [71,72], the leucine-rich repeat kinase LRRK2/PARK8 are crucial for the maintenance of autophagy–lysosome pathway function [73] and lysosomal glucocerebrosidase [74,75].

DNA Methylation in PD

Many researchers opined that PD is a consequence of various genetic variants along with complex environment–gene interactions and age-related changes and presdisposing factors [76]. Recently few hypotheses were proposed that the altered DNA methylation also play a key role in the pathogenesis of PD.

Jowaed et al. [77] reported DNA methylation in the transcriptionally active intron1 of SNCA in PD patients’ brains. Whereas Cai et al. and De Mena et al. [78,79] reported that there is no alteration in the methylation levels of SNCA gene promoter and Tan et al. [80] found that the methylation levels of the leucine-rich repeat kinase 2 was not altered.

Dysregulation of iron metabolism

Recently Brain iron homeostasis recognized as one of the potential target in the development of drug therapies for neurodegenerative disorders. Actually Iron plays a major role in maintaining normal physiological functions in the brain through its participation in key cellular functions such as myelin synthesis, mitochondrial respiration and neurotransmitter synthesis. But, excess iron causes oxidative damage by free radical formation.

In recent studies a correlation between the accumulation of iron in glial cells and neurons of the Substantia Nigra with the severity of PD disease is identified [81]. Moreover, iron induces the conversion of α-synuclein to the β-sheet from the α-helix conformation which is a characteristic of the Lewy bodies present in SN of PD patients [82].

Iron chelation efficacy that reduces iron levels in PD has been investigated and this prevented toxicity in mouse model of PD [83]. But the main difficulty in using iron chelation is caused by the inability of large iron chelating molecules such as desferrioxamine in penetrating the Blood brain barrier. However relatively low molecular weight compounds such as clioquinol has been effective in treating dementia and Parkinsonism phenotypes in mouse [84,85].

A Risk Associated with Living in Rural Areas

Recent studies have considered the exposure to pesticides, well water use, especially in rural living scenarios as risk factor for developing Parkinson’s disease. People having Farming as an occupation were significantly associated with PD, but many studies have shown that there is no increased risk of PD with rural or farm residence or well water use. These observations conclude that Parkinson’s disease is linked with occupational exposure to herbicides and insecticides and also farming; however the risk of farming cannot be presented by pesticide exposure alone.

Symptoms

Motor symptomss

PD is associated with bradykinesia (slow movements), resting tremor (initially unilateral), rigidity, postural instability and shuffling gait. PD symptoms are progressive and the progressions are highly variable. Other symptoms include blurred vision, decreased eye blink rate, dystonia, impaired upward gaze, kyphosis, masked facial expression (hypomimia), speech impairment, stooped posture, palilalia (repetition of word or phrase) or hypophonia (increasingly soft voice), etc. Around 25-60% of PD patients experience freezing of movements after several years from PD onset [86].

Non-motor symptoms

Non-motor symptoms of PD pose greatest challenges to quality of PD patient’s life. These include autonomic nervous system failure, cognitive changes, neuropsychiatric changes, sensory and sleep disturbances. Recent studies have shown that around 90% of PD patients have non-motor symptoms during the course of PD. Problems with decision-making, memory retrieval, multi-tasking and visuospatial perception can also be seen in patient suffering with PD.

Probability of occurrence of hallucinations and Psychosis in PD patients is high. The most common psychotic symptom is visual hallucinations. Almost forty percent of drug-treated PD patients undergo some form of psychosis. All the anti-parkinsonian medications are shown to induce some form of psychosis.

Dementia of PD occurs in the later stages but early onset of dementia is seen in patients with a family background of PD. Mood disorders such as anxiety, depression and apathy also occur in PD patients. Mood disorders are the most troublesome non-motor symptoms in both the early and late PD patients and anxiety is the most frequent psychiatric mood disorder. Abulia (loss of ability to think or act) and apathy (loss of motivation) can also occur. Sleep disturbance, frequent waking during the night, early morning awakening, Rest tremors and sleep attacks. All these symptoms seriously erode quality of life of the PD patients. Autonomic disturbances such as constipation, dysphagia, fecal incontinence, orthostasis, urinary difficulties, sexual dysfunction, nocturia and urge incontinence sialorrhea (excessive salivation) are not uncommon in PD patients. PD also alters skin health by affecting micro RNAs that regulate protein-coding genes that are involved in wound healing and angiogenesis. Olfactory dysfunction and sensory symptoms of pain are also found in PD patients.

Diagnosis

Currently structural and functional neuroimaging studies such as 18F-fluorodeoxyglucose-positron emission tomography 18 (FDGPET), single-photon emission computed tomography, PET-computed tomography and magnetic resonance imaging are being employed in clinical diagnosis of neurodegenerative diseases [87].

Phosphorylated α-synuclein is associated with abnormal EEG wave spectra of brains in PD patients. Hence, in vivo EEG quantitative measures can be used as a valid biomarker of cognitive abnormalities in PD [88]. Cerebrospinal biomarkers are not yet identified for PD. However, in recent studies it was found that there is an increase in α-synuclein levels in L1CAM-positive vesicles in plasma of PD patients when compared with healthy individuals. Therefore, CNSderived extracellular vesicles have the potential to be developed as PD biomarkers [89]. Generally α-Synuclein is biochemically measured using ELISA or by immunoblots [90].

Treatment

Nuclear receptor Nurr1 plays an important role in the development of dopamine (DA) in midbrain neurons making the Nurr1 as a target for PD. In vitro and in vivo studies shown that Nurr1 gene therapy and Nurr1 activating compounds improves DA neurotransmission and protects DA neurons from toxic effects of neuroinflammation mediated by microglia or environmental toxins [91]. The retromer pathway has been emerged as one of the most efficient pathway implicated in PD. Deficiency of or mutation of VPS35 leads to the aggregation and accumulation of α-synuclein with degeneration of dopaminergic neurons and also causes mitochondrial dysfunction. Hence retromer pathway is a promising target for PD [92,93].

Dimethylfumarate (DMF) and monomethyl fumarate (MMF) offers neuroprotection through Nrf2-mediated antioxidant pathway and anti-inflammatory [94]. MMF’s neuroprotective effects will not involve the inhibition of mitochondrial functions, so oxidative damage due to mitochondrial dysfunction which is one of the main causes for the pathogenesis of PD can be averted by using MMF hence MMF can be used in developing a new therapy for PD.

Targeting synucleinopathies

Targeting of α-syn accumulation, such as its aggregation, synthesis, and clearance, can help in disease modification and lowering the symptoms and recent approaches focused on α-syn such as active and passive immunotherapy [95], degrading enzymes [96], anti-aggregation compounds [97], α-syn siRNA delivery [98], autophagy enhancers [99] and molecular chaperones [100]. Stimulating neurogenesis [101] and Regenerative therapy using stem cells [102] has gained much attention.

Oral L-dopa therapy

In all the stages of PD and with almost all types of complications treatment with L-Dopa is recommended. Uptake of L-Dopa into blood from the duodenum and to the brain competes with the uptake of neutral amino acids hence L-Dopa preparation should be 1 h before or after a meal.

Dopamine agonists

Dopamine agonists are used mainly in the early stages of PD as mono therapy or adjunct therapy (2a) along with L-Dopa therapy in the intermediate state of PD and along with L-Dopa (2b) in the advanced state PD. Five ergot and five non-ergot-derivates totally ten dopamine agonists are available for the treatment of PD. Ergot dopamine agonists include α-dihydroergocriptine, bromocriptine, cabergoline, pergolide and lisuride and piribedil, pramipexole, ropinirole and rotigotine are the non-ergot derivates. The main disadvantage of dopamine agonists especially will in the advanced stages of PD which results in the accelation of cognitive impairment or dementia, hallucinations.

Deep brain stimulation

Deep brain stimulation (DBS) especially in the subthalamic nucleus (STN), ventral intermediate nucleus (VIM), and globus pallidus pars internus (GPi) has been developed especially for the treatment of the motor symptoms of PD mainly for tremors at rest which is resistant to pharmacotherapy.

Other compounds

Caffeine: Many studies have shown that Drinking coffee reduces the risk of developing PD [103]. Caffeine intake has shown symptomatic benefits in PD patients [104].

Inosine: Inosine is a precursor molecule of urate and its administration leads to increase in serum urate levels. Elevated Urate levels increases the antioxidant activity in substantia nigra pars compacta dopaminergic neurons and protects against 6-OHDA toxicity [105]. Some studies proved that Inosine is safe and triggers urate levels in cerebro spinal fluid and serum which decelerates PD progression [106].

Nicotine: Epidemiological Studies during the last few decades have shown an inverse relation between PD susceptibility and tobacco consumption. PD is found to be less prevalent among smokers than non-smokers [107]. Nicotine up-regulates anti-apoptotic proteins which prevents or slows down the neurodegeneration [108]. Nicotine activates the enzymes of the cytochrome P450 family which detoxifys neurotoxins [109]. Studies on non-human primates have shown that Nicotine protects from toxin-induced nigrostriatal degeneration [110].

Herbs: Many herbs have shown potential in the treatment of PD symptoms or to reduce the PD progression. Herbs such as Acanthopanax (Eleutherococcus maxim), Alpinia (A. galanga), Astragalus, Camellia (C. sinensis), Cassia (Cinnamomum fragrans), Chrysanthemum (Chrysanthemum morifolium), Cistanche, Cuscuta (Cuscuta L.), Fraxinus (Fraxinus excelsior), Gastrodia (G. elata), Ginkgo (Ginkgo biloba), Gynostemma (Gynostemma pentaphyllum), Polygonum (Polygonum multiflorum), Pueraria (Pueraria mirifica), Rhodiola (Rhodiola rosea), Scutellaria, Tripterygium (Tripterygium wilfordii), etc. have potential neuro protective properties.

Currently there is no treatment that could completely cure Parkinson’s disease, but very few treatments are available that help in relieving the symptoms and maintaining the quality of life. The conclusions published in the journal Nature Communications, present a better understanding and provide scope for further research towards a possible cure or treatment of Parkinson’s disease. Despite of the advances in understanding the causes of familial forms of this disease, the idiopathic form of Parkinson’s disease which is the most prevalent still remains a mystery.

Conclusion

PD is one of the most common neurodegenerative diseases mostly seen in later ages of life. A combination of environmental and genetic factors is responsible for the abnormal protein aggregation in some specific group of neurons, leading to their dysfunction and eventually death. Genetic factors involving the methylation of DNA affecting genes in the function of mitochondria are found to be one of the most important causes for the pathogenesis of PD. Identifying biomarkers for early detection of PD in humans will undoubtedly improve the early stage therapeutics like immunotherapy. However, efforts in the development of effective alternative treatments for PD and related neurodisorders have increased recently. Logical combination of therapies can be a potent approach for treating synucleinopathies. In the next decade we can see a rise of personalized medicine for the treatment of PD, including familial and sporadic with disease-modifying approaches.

References

1. Dua T (2004) Atlas: Country resources for neurological disorders 2004: Results of a collaborative study of the World Health Organization and the World Federation of Neurology. Programme for Neurological Diseases and Neuroscience, Department of Mental Health and Substance Abuse. World Health Organization, Geneva.
2. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276: 2045-2047.
3. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, et al. (1997) Alpha-synuclein in Lewy bodies. Nature 388: 839-840.
4. Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9: 13-24.
5. Lewy FH (1992) Paralysis agitans. I. Pathologische Anatomie. In Handbuch der Neurologie. Ed Lewandowski M. Berlin: Springer 920-933.
6. Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 51: 745-752.
7. Gibb WR, Lees AJ (1989) The significance of the Lewy body in the diagnosis of idiopathic Parkinson's disease. Neuropathol Appl Neurobiol 15: 27-44.
8. Lowe J (1994) Lewy bodies. In DP Calne. Ed N Diseases. Philadelphia: Saunders, pp: 51-69.
9. Braak H, Braak E, Yilmazer D, de Vos RA, Jansen EN, et al. (1994) Amygdala pathology in Parkinson's disease. Acta Neuropathol 88: 493-500.
10. Braak H, Sandmann-Keil D, Gai WP, Braak E (1999) Extensive axonal Lewy neurites in Parkinson's disease: A novel pathological feature revealed by a-synuclein immunocytochemistry. Neurosci Lett 265: 67-69.
11. Dickson DW, Schmidt ML, Lee VM, Zhao ML, Yen SH, et al. (1994) Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. Acta Neuropathol 87: 269-276.
12. Gai WP, Blessing WW, Blumbergs PC (1995) Ubiquitin-positive degenerating neurites in the brainstem in Parkinson's disease. Brain 118: 1447-1459.
13. Takahashi H, Wakabayashi K (2001) The cellular pathology of Parkinson's disease. Neuropathology 21: 315-322.
14. Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy bodies: Dissimilar incorporation of alpha-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol 62: 1241-1253.
15. Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, et al. (2003) Accumulation of phosphorylated alpha-synuclein in aging human brain. J Neuropathol Exp Neurol 62: 644-654.
16. Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9: 13-24.
17. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, et al. (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24: 197-211.
18. Boeve BF (2013) Idiopathic REM sleep behaviour disorder in the development of Parkinson's disease. Lancet Neurol 12: 469-482.
19. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res 318: 121-134.
20. Dickson DW, Uchikado H, Fujishiro H, Tsuboi Y (2010) Evidence in favor of Braak staging of Parkinson's disease. Mov Disord 25 Suppl 1: S78-82.
21. Halliday G, McCann H, Shepherd C (2012) Evaluation of the Braak hypothesis: How far can it explain the pathogenesis of Parkinson's disease? Expert Rev Neurother 12: 673-686.
22. Uchihara T, Giasson BI (2016) Propagation of alpha-synuclein pathology: Hypotheses, discoveries and yet unresolved questions from experimental and human studies. Acta Neuropathol 131: 49-73.
23. Braak H, Del Tredici K (2009) Neuroanatomy and pathology of sporadic Parkinson's disease. Adv Anat Embryol Cell Biol 201: 1-119.
24. Braak H, Rüb U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson's disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110: 517-536.
25. Saper CB, Wainer BH, German DC (1987) Axonal and transneuronal transport in the transmission of neurological disease: Potential role in system degenerations, including Alzheimer's disease. Neuroscience 23: 389-398.
26. Sacino AN, Brooks J, Thomas MA, McKinney AB, Lee S, et al. (2014) Intramuscular injection of a-synuclein induces CNS a-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci USA 111: 10732-10737.
27. Phillips RJ, Walter GC, Wilder SL, Baronowsky EA, Powley TL (2008) Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: Autonomic pathway implicated in Parkinson's disease? Neuroscience 153: 733-750.
28. Norrian AR, Rha J, Annerino DM, Bernhard D, Taylor GM, et al. (2012) Alpha-synuclein transgenic mice display age-related slowing of gastrointenstinal motility associated with transgene expression in the vagal system. Neurobiol Dis 48: 9-19.
29. Svensson E, Horváth-Puhó E, Thomsen RW, Djurhuus JC, Pedersen L, et al. (2015) Vagotomy and subsequent risk of Parkinson's disease. Ann Neurol 78: 522-529.
30. Kim WS, Kågedal K, Halliday GM (2014) Alpha-synuclein biology in Lewy body diseases. Alzheimers Res Ther 6: 73.
31. Dehay B, Bourdenx M, Gorry P, Przedborski S, Vila M, et al. (2015) Targeting a-synuclein for treatment of Parkinson's disease: Mechanistic and therapeutic considerations. Lancet Neurol 14: 855-866.
32. Lamberts JT, Hildebrandt EN, Brundin P (2015) Spreading of α-synuclein in the face of axonal transport deficits in Parkinson's disease: A speculative synthesis. Neurobiol Dis 77: 276-283.
33. Reichmann H (2011) View point: Etiology in Parkinson's disease. Dual hit or spreading intoxication. J Neurol Sci 310: 9-11.
34. Pan-Montojo F, Reichmann H (2014) Considerations on the role of environmental toxins in idiopathic Parkinson's disease pathophysiology. Transl Neurodegener 3: 10.
35. Brundin P, Li JY, Holton JL, Lindvall O, Revesz T (2008) Research in motion: The enigma of Parkinson's disease pathology spread. Nat Rev Neurosci 9: 741-745.
36. Angot E, Steiner JA, Hansen C, Li JY, Brundin P (2010) Are synucleinopathies prion-like disorders? Lancet Neurol 9: 1128-1138.
37. Goedert M, Clavaguera F, Tolnay M (2010) The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 33: 317-325.
38. Goedert M, Falcon B, Clavaguera F, Tolnay M (2014) Prion-like mechanisms in the pathogenesis of tauopathies and synucleinopathies. Curr Neurol Neurosci Rep 14: 495.
39. Steiner JA, Angot E, Brundin P (2011) A deadly spread: Cellular mechanisms of a-synuclein transfer. Cell Death Differ 18: 1425-1433.
40. Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, et al. (2012) Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 7: 42.
41. Dunning CJ, Reyes JF, Steiner JA, Brundin P (2012) Can Parkinson's disease pathology be propagated from one neuron to another? Prog Neurobiol 97: 205-219.
42. Hansen C, Li JY (2012) Beyond α-synuclein transfer: pathology propagation in Parkinson's disease. Trends Mol Med 18: 248-255.
43. Bousset L, Pieri L, Ruiz-Arlandis G, Gath J, Jensen PH, et al. (2013) Structural and functional characterization of two alpha-synuclein strains. Nat Commun 4: 2575.
44. George S, Rey NL, Reichenbach N, Steiner JA, Brundin P (2013) a-Synuclein: The long distance runner. Brain Pathol 23: 350-357.
45. Jucker M, Walker LC (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501: 45-51.
46. Olanow CW, Brundin P (2013) Parkinson's disease and alpha synuclein: Is Parkinson's disease a prion-like disorder? Mov Disord 28: 31-40.
47. Sacino AN, Giasson BI (2012) Does a prion-like mechanism play a major role in the apparent spread of a-synuclein pathology? Alzheimers Res Ther 4: 48.
48. Luk KC, Lee VM (2014) Modeling Lewy pathology propagation in Parkinson's disease. Parkinsonism Relat Disord 20 Suppl 1: S85-87.
49. Recasens A, Dehay B (2014) Alpha-synuclein spreading in Parkinson's disease. Front Neuroanat 8: 159.
50. Tran HT, Chung CH, Iba M, Zhang B, Trojanowski JQ, et al. (2014) A-synuclein immunotherapy blocks uptake and templated propagation of misfolded a-synuclein and neurodegeneration. Cell Rep 7: 2054-2065.
51. Herva ME, Spillantini MG (2015) Parkinson's disease as a member of Prion-like disorders. Virus Res 207: 38-46.
52. Melki R (2015) Role of different alpha-synuclein strains in synucleinopathies, similarities with other neurodegenerative diseases. J Parkinson's Dis 5: 217-227.
53. Peelaerts W, Bousset L, Van der Peren A, Moskalyuk A, Pulizzi R, et al. (2015) a-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522: 340-344.
54. Kamel F, Goldman SM, Umbach DM, Chen H, Richardson G, et al. (2014) Dietary fat intake, pesticide use, and Parkinson's disease. Parkinsonism Relat Disord 20: 82-87.
55. Chaturvedi RK, Beal MF (2008) Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 1147: 395-412.
56. Borland MK, Trimmer PA, Rubinstein JD, Keeney PM, Mohanakumar K, et al. (2008) Chronic, low-dose rotenone reproduces Lewy neurites found in early stages of Parkinson's disease, reduces mitochondrial movement and slowly kills differentiated SH-SY5Y neural cells. Mol Neurodegener 3: 21.
57. Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58: 495-505.
58. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443: 787-795.
59. Maio DI, Barrett PJ, Hoffman EK, Barrett CW, Zharikov AV, et al. (2016) a-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Sci Transl Med 8: 342ra378.
60. Thomas B, Beal MF (2007) Parkinson's disease. Hum Mol Genet 16 Spec No.
61. Thomas B, Beal MF (2010) Mitochondrial therapies for Parkinson's disease. Mov Disord 25 Suppl 1: S155-160.
62. Pickrell AM, Youle RJ (2015) The roles of PINK1, parkin and mitochondrial fidelity in Parkinson's disease. Neuron 85: 257-273.
63. Lesage S, Drouet V, Majounie E, Deramecourt V, Jacoupy M, et al. (2016) Loss of VPS13C function in autosomal-recessive Parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy. Am J Hum Genet 98: 500-513.
64. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, et al. (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 361: 1651-1661.
65. Osellame LD, Rahim AA, Hargreaves IP, Gegg ME, Richard-Londt A, et al. (2013) Mitochondria and quality control defects in a mouse model of Gaucher disease–links to Parkinson's disease. Cell Metab. 17: 941-953.
66. Gitler AD, Bevis BJ, Shorter J, Strathearn KE, Hamamichi S, et al. (2008) The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci U S A 105: 145-150.
67. Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, et al. (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329: 1663-1667.
68. Gan-Or Z, Dion PA, Rouleau GA (2015) Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 11: 1443-1457.
69. Bourdenx M, Bezard E, Dehay B (2014) Lysosomes and a-synuclein form a dangerous duet leading to neuronal cell death. Front Neuroanat 8: 83.
70. Krüger R, Sharma M, Riess O, Gasser T, Van Broeckhoven C, et al. (2011) A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease.  Neurobiol Aging 32: 548.
71. Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, et al. (2013) Lysosomal impairment in Parkinson's disease. Mov Disord 28: 725-732.
72. Hunn BH, Cragg SJ, Bolam JP, Spillantini MG, Wade-Martins R (2015) Impaired intracellular trafficking defines early Parkinson's disease. Trends Neurosci 38: 178-188.
73. Laguna A, Schintu N, Nobre A, Alvarsson A, Volakakis N, et al. (2015) Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease. Nat Neurosci 18: 826-835.
74. Siebert M, Sidransky E, Westbroek W (2014) Glucocerebrosidase is shaking up the synucleinopathies. Brain 137: 1304-1322.
75. Schapira AH (2015) Glucocerebrosidase and Parkinson disease: Recent advances. Mol Cell Neurosci 66: 37-42.
76. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J (2011) Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur J Epidemiol 26 Suppl 1: S1-58.
77. Jowaed A, Schmitt I, Kaut O, Wüllner U (2010) Methylation regulates alpha-synuclein expression and is decreased in Parkinson's disease patients' brains. J Neurosci 30: 6355-6359.
78. Cai M, Tian J, Zhao GH, Luo W, Zhang BR (2011) Study of methylation levels of parkin gene promoter in Parkinson's disease patients. Int J Neurosci 121: 497-502.
79. De Mena L, Cardo LF, Coto E, Alvarez V, Coto E (2013) No differential DNA methylation of PARK2 in brain of Parkinson's disease patients and healthy controls. Mov Disord 28: 2032-2033.
80. Tan YY, Wu L, Zhao ZB, Wang Y, Xiao Q, et al. (2014) Methylation of α-synuclein and leucine-rich repeat kinase 2 in leukocyte DNA of Parkinson's disease patients. Parkinsonism Relat Disord 20: 308-313.
81. Pyatigorskaya N, Sharman M, Corvol JC (2015) High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry. Mov Disord 30: 1077-1084.
82. el-Agnaf OM, Irvine GB (2002) Aggregation and neurotoxicity of alpha-synuclein and related peptides. Biochem Soc Trans 30: 559-565.
83. Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, et al. (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: A novel therapy for Parkinson's disease. Neuron 37: 899-909.
84. Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, et al. (2012) Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 18: 291-295.
85. Lei P, Ayton S, Appukuttan AT, Volitakis I, Adlard PA, et al. (2015) Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse. Neurobiol Dis 81: 168-175.
86. Virmani T, Moskowitz CB, Vonsattel JP, Fahn S (2015) Clinicopathological characteristics of freezing of gait in autopsy-confirmed Parkinson's disease. Mov Disord 30: 1874-1884.
87. Al-Radaideh AM, Rababah EM (2016) The role of magnetic resonance imaging in the diagnosis of Parkinson's disease: A review. Clin Imaging 40: 987-996.
88. Caviness JN, Lue LF, Hentz JG, Schmitz CT, Adler CH, et al. (2016) Cortical phosphorylated a-Synuclein levels correlate with brain wave spectra in Parkinson's disease. Mov Disord 31: 1012-1019.
89. Lööv C, Scherzer CR, Hyman BT, Breakefield XO, Ingelsson M (2016) a-Synuclein in extracellular vesicles: Functional implications and diagnostic opportunities. Cell Mol Neurobiol 36: 437-448.
90. Poehler AM, Xiang W, Spitzer P, May VE, Meixner H, et al. (2014) Autophagy modulates SNCA/a-synuclein release, thereby generating a hostile microenvironment. Autophagy 10: 2171-2192.
91. Dong J, Li S, Mo JL, Cai HB, Le WD (2016) Nurr1-based therapies for Parkinson's disease. CNS Neurosci Ther 22: 351-359.
92. Tang FL, Erion JR, Tian Y, Liu W, Yin DM, et al. (2015a) VPS35 in dopamine neurons is required for endosome-to-Golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for a-synuclein degradation and prevention of pathogenesis of Parkinson's disease. J Neurosci 35: 10613-10628.
93. Tang FL, Liu W, Hu JX, Erion JR, Ye J, et al. (2015) VPS35 deficiency or mutation causes dopaminergic neuronal loss by impairing mitochondrial fusion and function. Cell Rep 12: 1631-1643.
94. Ahuja M, Ammal Kaidery N, Yang L, Calingasan N, Smirnova N, et al. (2016) Distinct Nrf2 signaling mechanisms of fumaric acid esters and their role in neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced experimental Parkinson's-like disease. J Neurosci 36: 6332-6351.
95. Valera E, Masliah E (2013) Immunotherapy for neurodegenerative diseases: Focus on a-synucleinopathies. Pharmacol Ther 138: 311-322.
96. Devi L, Ohno M (2015) A combination Alzheimer's therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice. Mol Brain 8: 19.
97. Wobst HJ, Sharma A, Diamond MI, Wanker EE, Bieschke J (2015) The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett 589: 77-83.
98. ooper JM, Wiklander PB, Nordin JZ, Al-Shawi R, Wood MJ, et al. (2014) Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov Disord 29: 1476-1485
99. Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ (2012) The role of autophagy in Parkinson's disease. Cold Spring Harb Perspect Med 2: a009357.
100. Voss K, Combs B, Patterson KR, Binder LI, Gamblin TC (2012) Hsp70 alters tau function and aggregation in an isoform specific manner. Biochemistry 51: 888-898.
101. Foltynie T (2015) Can Parkinson's disease be cured by stimulating neurogenesis? J Clin Invest 125: 978-980.
102. Schwerk A, Altschüler J, Roch M, Gossen M, et al. (2015) Adipose-derived human mesenchymal stem cells induce long-term neurogenic and anti-inflammatory effects and improve cognitive but not motor performance in a rat model of Parkinson's disease. Regen Med 10: 431-446.
103. Costa J, Lunet N, Santos C, Santos J, Vaz-Carneiro A (2010) Caffeine exposure and the risk of Parkinson's disease: A systematic review and meta-analysis of observational studies. J Alzheimers Dis 20 Suppl 1: S221-238.
104. Wills AM, Eberly S, Tennis M, Lang AE, Messing S, et al. (2013) Caffeine consumption and risk of dyskinesia in CALM-PD. Mov Disord 28: 380-383.
105. Zhang N, Shu HY, Huang T, Zhang QL, Li D, et al. (2014) Nrf2 signaling contributes to the neuroprotective effects of urate against 6-OHDA toxicity. PLoS One 9: e100286.
106. Bhattacharyya S, Bakshi R, Logan R, Ascherio A, Macklin EA, et al. (2016) Oral inosine persistently elevates plasma antioxidant capacity in Parkinson's disease. Mov Disord 31: 417-421.
107. Quik M (2004) Smoking, nicotine and Parkinson's disease. Trends Neurosci 27: 561-568.
108. Dasgupta P, Kinkade R, Joshi B, Decook C, Haura E, et al. (2006) Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin. Proc Natl Acad Sci U S A 103: 6332-6337.
109. Miksys S, Tyndale RF (2006) Nicotine induces brain CYP enzymes: relevance to Parkinson's disease. J Neural Transm Suppl, pp: 177-180.
110. Quik M, Parameswaran N, McCallum SE, Bordia T, Bao S, et al. (2006) Chronic oral nicotine treatment protects against striatal degeneration in MPTP-treated primates. J Neurochem 98: 1866-1875.