First described as a “shaking palsy” by James Parkinson in the early 1800’s, Parkinson’s disease is a common neurodegenerative disorder. It primarily affects the motor system, though does often lead to some cognitive impairment. Symptoms include stiffness, loss of fine motor skills, shuffling feet, altered mood and impaired memory. The reduction in motor skills is termed akinesia, which again is broadly divided into two forms: bradykinesia (slowness in executing movements) and hypokinesia (lack of spontaneous movement). The disease is progressive, with symptoms developing over a number of years and eventually leading to severe disability and reliance on caregivers. Perhaps the most debilitating consequence of Parkinson’s is also the hallmark of the disease – tremor that vibrates at 4-6 Hertz. Additionally, in post-mortem sections of the brain, protein deposits (termed Lewy bodies) are seen. These deposits cause degeneration of brain tissue, notably dopamine-producing neurons, that cause the aforementioned symptoms.

Around 127,000 people in the United Kingdom are affected by Parkinson’s, with a global patient population of around 10 million (Rousseaux, Shulman and Jankovic, 2017). Incidence is strongly correlated with age: in developed countries, Parkinson’s presents in 0.3% of the population (De Lau and Breteler, 2006). This increases to 3.5% in those aged eighty-five to eighty-nine (Clarke and Moore, 2007).

Around 10% of all Parkinson’s cases are believed to have a genetic basis, with mutations in three genes (alpha-synuclein, SCNA; glucocerebroxidase, GBA, and leucine-rich repeat kinase 2, LRRK2) leading to substantially increased risk. Recent genome-wide association studies (GWAS) have led to the identification of a further 20 susceptibility alleles (Rousseaux, Shulman and Jankovic, 2017). The alleles may act combinatorially: how Parkinson’s presents clinically can vary dramatically from patient to patient, as can the age of onset and speed at which symptoms progress. Having a more comprehensive understanding of the multifactorial genetic basis to the disease will help improve patient outcome by facilitating “personalised” treatments.

Particularly strong correlations have been made between early-onset Parkinson’s disease (EOPD) and genetics. Around 3.6% of Parkinson’s patients have an early-onset variant of the condition, developing symptoms before their mid-forties (Kilarski et al., 2012). Three genes in particular are linked with EOPD, each acting in an autosomal recessive manner. PARK2 encodes parkin, an E3 ubiquitin protein ligase associated with mitochondrial function whilst PINK encodes a serine/threonine protein kinase. PARK7 encodes DJ-1, a protein involved in a variety of cellular processes ranging from transcriptional control to mitochondrial regulation (Ariga et al., 2013).

Despite the promise of GWAS and associated techniques, the fact remains that over 90% of PD cases are idiopathic. Some links have been established between certain environmental factors and increased risk of developing Parkinson’s. Exposure to pesticides, for example, appears to lead to an increased incidence of Parkinson’s in farmers and other agricultural workers. It is believed that the pesticides inhibit ALDH, believed to have a role in neuronal protection (Fitzmaurice et al, 2014). The interaction between the pesticides and ALDH appears to allele-specific, with some variants of the gene increasing risk more than others.  This highlights the importance of conducting more gene-environment studies when trying to elucidate the cause of diseases such as Parkinson’s, which often present without any discernible cause.

Alpha-synuclein is a 140 residue, intrinsically unstructured protein that localises to presynaptic terminals. Though the normal biological function of a-synuclein largely unknown, it is believed to have some role in supplying vesicles to synapses. However, knock-out organisms show few deleterious phenotypes. Amongst all this uncertainty, one fact has been established: rare variants of the protein precipitate out of solution and form pathological aggregates termed Lewy bodies. Little is known about the induction of these aggregates, though there are many theories. For instance, alpha-synuclein often undergoes post-translational nitration, which is enhanced in stressful conditions. Increased nitration has been linked to higher levels of Lewy bodies is tissues (Glasson et al., 2000).

Additionally, environmental factors are believed to be linked with the induction of Lewy bodies. Head traumas and associated injuries in particular have long been considered an important factor in predicting the development of a range of neurodegenerative diseases. One meta-analysis suggested that the risk of developing Parkinson’s rose threefold if the patient had sustained a traumatic brain injury earlier in life (Crane et al., 2016). Interestingly, in vitro Lewy bodies can be generated through constant aggitation at room temperature for five days. Though not exactly analogous to in vivo conditions, the findings do lend some support the trauma theory (Volpicelli-Daley et  al.,2011).

Ultimately, these precipitates are lethal to neurons and cause a range of disordered termed “synucleopathies”

Parkinson’s disease is one such synucleopathy, and the progression of the disease can be characterised by six stages based on the formation of Lewy bodies in the brain (Robinson, 2005). Interestingly, in at least some cases of sporadic Parksinson’s, the origin of the Lewy bodies is not the brain: rather, they initially form in the enteric nervous system (Braak et al., 2006). They then spread through the central nervous system before reaching the brain stem. From here, the precipitates first affect the medulla oblongata, and in the later stages spread to the substantia nigra and lower raphe nuclei before finally reaching to the amygdala and the cortex. The latter two are centres of emotion, language, perception and cognition, and their loss explains why many late-stage Parkinson’s patients also suffer from dementia. Neurons involved in olfaction are also disproportionally affected in the early stages of Parkinson’s, with hyposmia (the loss of the ability to smell) being one of the primary pre-motor symptoms of the disease (Xiao, Chen and Le, 2014).

Given the fact that a-synuclein accumulation is a primary biomarker of Parkinson’s disease, it can be expected that mutations in the encoding gene – the aforementioned SNCA – would affect an individual’s chances of developing the disease. Thus far, association studies indicate that missense mutations in the gene are quite rare in the population (Berg et al., 2005). Nevertheless, five such mutations have been associated with familial autosomal dominant Parkinson’s (Siddiqui, Pervaiz and Abbasi, 2016). These mutations – A30P, E46K, H50Q, G51D and A53T – all appear to inhibit p53 expression. P53 induces apoptosis in cells, so the fact that these mutations reverse that effect suggests that wild-type alpha-synculein has a neuroprotective, antiapoptotic role in cells (da Costa, Ancolio and Checler, 2000).

Regardless of whether the case is familial or sporadic, the defining feature of Parkinson’s disease is the tremor. Initially, the tremor will affect the initiation or execution of movements, though 70% of those with advanced Parkinson’s also suffer from a resting tremor (Baumann, 2012). All classes of affected movement are ultimately caused by a loss of dopaminergic neurons. These are primarily located in the substantia nigra, an area disproportionately affected by the accumulation of Lewy bodies. Dopamine is a neuromodulator involved in pleasure, planning and – importantly in Parkinson’s disease – motor ability. It is synthesised from a tyrosine precursor, which is converted to L-DOPA by tyrosine hydroxylase. L-DOPA is subsequently converted to dopamine by DOPA decarboxylase. This enzyme is widespread throughout the brain, despite the fact that dopamine synthesis itself is highly localised to the substantia nigra.

Loss of the dopamine neurons has dramatic effects on the brain. The motor control (nigrostriatal system) is affected, as is the behavioural control system. Dopamine can be seen as the brain’s “motivational chemical”. By modulating the excitability of the glutamate synapses, it helps control decisiveness over relatively simple tasks (such as picking up a pen). Without dopamine, the brain is unable to initiate movements.

The link between a lack of dopamine and PD was initially demonstrated by inhibiting dopamine synthesis using reserpine. When injected with reserpine, rats were unable to move and were limp. However, when injected with L-DOPA, they regained their ability to move (Colpaert, 1987). Though dopamine synthesis is confined to the sunstantia nigra, the requisite enzyme – dopamine carboxylase – is spread throughout the brain, so injections of the dopamine precursor can be used to increase dopamine synthesis in the brain. This discovery paved the way for initial treatments for Parksinon’s disease.

Nevertheless, there is still no long-term cure for those with the condition. For many, if diagnosed early, prognoses can be good, and life expectancy between those with and without the condition is not significantly different. However, the difference in quality of life can be quite dramatic, with many Parkinson’s patients experiencing severe debilitation as they age. Ongoing research has provided some hope, but sustained – and, preferably, increased – funding is required to fully understand this complex disease. This is especially true when considering the rapid rate at which the population is aging, as the disease’s prevalence is society is only set to increase.


Ariga, H., Takahashi-Niki, K., Kato, I., Maita, H., Niki, T., and Iguchi-Ariga, S.M.M. (2013). Neuroprotective function of DJ-1 in Parkinson’s disease. Oxidative Medicine and Cellular Longevity. 2013:

Baumann, C.R. (2012). Epidemiology, diagnosis and differential diagnosis in Parkinson’s disease tremor. Parkinsonism Related Disorders 18:s90-s92

Berg, D., Niwar, M., Maass, S., Zimprich, A., Carsten Möller, J., Wuellner, U., Schmitz-Hübsch, T., Klein, C., Tan, E.-K., Schöls, L., Marsh, L. Dawson, T.M., Janetzky, B., Müller, T., Woitalla, D. Kostic, V., Pramstaller, P.P., Oertel, W.H., Bauer, P., Krueger, R., Gasser, T. and Reiss, O. (2005). Alpha-synculein

Braak, H., de Vos, R.A., Bohl, J. and Del Tredici, K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology (2006). Neuroscience Letters 396:67-72

Clarke, C.E. and Moore, A., P. (2007). Parkinson’s disease. BMJ Clinical Evidence 1203

Colpart, F.C. (1987). Pharmacological characteristics of tremor, rigidity and hypokinesia induced by reserpine in rat. Neuropharmacology26:1431-2440

Crane, P.K., Gibbons, L.E., Dams-O’Connor, K., Trittschuh, E., Leverenz, J.B., Keene, C.D., Sonnen, J., Montine, T.J., Bennett, D.A., Leurgans, S., Schneider, J.A. and Larson, E.B. (2016). Association of traumatic brain injury with late-life neurodegenerative conditions and neuropathological findings. JAMA Neurology 73:1062-1069

Da Costa, C.A., Ancolio, K. & Checler, F. (2000). Wild-type but not Parkinson’s disease-related ala-53 -> Thr mutant alpha-synuclein protects neuronal cells from apoptotic stimuli. Journal of Biological Chemistry 275:24065-34069

De Lau, L.M. and Breteler, M.M. (2006). Epidemiology of Parkinson’s disease. Lancet Neurology 5:525-535

Glasson, B.I., Duda, J.E., Murray, I.V., Chen, Q., Souza, J.M., Hurtig, H.I., Ischiropoulos, H., Trojanowski, J.Q. and Lee, V.M. (2000). Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985-989

Fitzmaurice, A.G., Rhodes, S.L., Cockburn, M., Ritz, B. and Bronstein, J.M. (2014). Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease. Neurology 82:419-426

Kilarski, L.L., Pearson, J.P., Newsway, V., Majounie, E., Knipe, M.D.W., Misbahuddin, A., Chinnery, P.F., Burn, D.J., Clarke, C.E., Marion, M.-H., Lewthwaite, A.J., Nicholl, D.J., Wood, N.W., Morrison, K.E., Williams-Gray, C.H., Evans, J.R., Sawcer, S.J., Barker, R.A., Wickremaratchi, M.M., Ben-Schlomo, Y., Williams, N.M. and Morris, H.R. (2012). Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson’s disease. Movement Disorders 27:1522-1529

Robinson, R. (2005).  The six neuropathological stages of Parkinson Disease. Neurology Today 5:45-46

Rousseaux, M.W.C., Shulman, J.M. and Jankovic, J. (2017). Progress toward an integrated understanding of Parkinson’s disease.F1000 Research 6:1121

Siddiqui, I.J., Pervaiz, N. and Abbasi, A.A. (2016). The Parkinson Disease gene SNCA: Evolutionary and structural insights with pathological implication. Scientific Reports 6:doi:10.1038/srep24475

Volpicelli-Daley, L.A., Luk, K.C., Patel, T.P., Tanik, S.A., Riddle, D.M., Stieber, A., Meany, D.F., Trohanowski, J.Q. and Lee, V. M.-Y. (2012) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57-71

Xiao, Q., Chen, S. and Le, W. (2014). Hyposmia: a possible biomarker of Parkinson’s disease. Neuroscience Bulletin 30:134-140

About the Author

Rachel Murray-Watson is currently pursuing a PhD in Cambridge University. Rachel obtained a first class honours (BSc) in Biological Sciences from Imperial College, London. Her thesis was on “Modelling the Spatial Spread of Gene Drives” and she won the Howarth Prize for excellence in plant sciences. Rachel won the Institute of Biology’s prize for 1st place in biology in the national examinations in Ireland. Her current area of research is mitigating the impact of communicable agriculural diseases by developing effective control strategies.