Is Parkinson’s Disease One Disease Entity?




Silhouette of elderly man

We hear of Parkinson’s disease very often these days. This is indeed a very common neurological disorder affecting about 6 million people worldwide. The disease is characterized by a selective loss of dopaminergic neurons in certain parts of the brain. That causes muscle rigidity, tremors, bradykinesia (slowness of movement) and problems in posture.

Decades of research brought some treatments that can delay the onset of Parkinson’s disease and try to counterbalance the endogenous dopamine deficit. Unfortunately, we still don’t have a treatment capable to stop the neuronal death and provide cure for the disease.

The current mainstream treatments for Parkinson’s disease were introduced around thirty years ago. They focused on dopamine systems and motor symptoms of advanced disease, and included dopatherapy with dopamine agonists and a monoamine oxidase B inhibitor selegiline. More agonists and inhibitors were introduced over the years, but the basic approach did not change. Parkinson’s disease still remains a serious condition leading to disability. Newer molecular targets, bio-markers and better understanding of molecular mechanisms of this condition are necessary.

The fact that our understanding of Parkinson’s disease is very limited is clearly indicated by the fact that not all patients respond to the existing treatments such as levodopa, major dopamine agonist in clinical practice. Part of the answer to the question why some patients respond to the existing treatments and others don’t lies in the fact that Parkinson’s disease is really an umbrella term for a number of conditions with similar symptoms. Diagnosis of disease is still based on the descriptive definition provided by James Parkinson almost 200 years ago.  The conditions covered by this description, however, are not all the same and can be caused by very different genetic and environmental factors. This has obvious implications for the development and application of any potential drugs targeting the disease.

Small portion (about 10%) of all Parkinson’s cases are related to genetics. Mutations in several genes were identified as risk factors in the development of the condition. The involvement of three genes, Parkin, PINK1 and DJ1, in the disease pathogenesis seems to be linked to their neuroprotective properties. They encode proteins that counteract oxidative stress, prevent damage to mitochondrial DNA and are essential for effective work of the ubiquitin-proteasome system. However, this is not specific for the Parkinson’s disease. These three gene products play equally critical role in a wide spectrum of neurodegenerative disorders. Is there anything more specific that can cause Parkinson’s disease, rather than any other neurodegeneration, in either humans or animals?

It seems that Parkinson’s disease pathogenesis requires not only the genetic susceptibility, but also environmental exposures to harmful chemicals and ageing. Genetic factors alone are not enough to cause the disease. In 90% of cases, the disease is sporadic without any clear genetic basis.

Current evidences suggest that oxidative stress, abnormal protein aggregation and mitochondrial disfunction are possible early triggers of cell death in Parkinson’s disease.  Parkinson’s disease can be induced by mitochondrial toxins MTPT and its metabolite MPP+, as well as pesticides rotenone and paraquat in both animals and humans.

Lewy bodies are abnormal aggregates of proteins observed inside the nerve cells of Parkinson’s patients. The formation of alpha-synuclein and tau inclusions in Lewy bodies in certain neurons is the most distinctive anatomical feature of the disease. Cell death in Parkinson’s disease is connected to both oxidative stress and accumulation of alpha-synuclein. Abnormal accumulation of alpha-synuclein can also produce oxidative damage to both mitochondria and dopamine.

However, neither Lewy bodies nor alpha-synuclein and tau inclusions are exclusive for Parkinsonism. They are seen in the broad spectrum of other neurologic condition broadly classified as synucleopathies, tauopathies and Lewy body disorder on the basis of presence of the above characteristic features. In Parkinson’s disease, these individual pathological features can be present in some patients and absent in others.

It seems that more diagnostic categories will be required in the future to properly characterize the sub-classes of Parkinson’s disease. What is now called “Parkinsonism” can include clinical Parkinson’s Syndrome, Lewy Body Parkinson’s Disease, several Lewy Body disorders and  synucleinopathies, and taupathies with various aetiology.

The Queen Square Brain Bank for Neurological Disorders (QSBB) has issued the list of criteria that should be used for clinical diagnostics of Parkinson’s disease. It includes (a) clinical diagnostics criteria, (b) genetic testing for mutations in alpha-synuclein gene SNCA in patients with family history of disease; mutations in  leucine-rich repeat kinase 2 (LPRK2) and  glucocerebrosidase (GPA) in sporadic patients; testing of parkin, PINK1 and DJ-1 in patients with early onset of the condition, with additional testing of several genes if these come out negative, (c) panel of various tests (neuroimaging), and (d) response to levodopa. This long list alone is in itself a manifestation of the fact that Parkinson’s disease can be caused or triggered by a variety of factors and therefore cannot be considered as just a single disease entity.

In the diagnostics of Parkinsonism, the DNA analysis must become a compulsory element. Improved sub-typing on the basis of genetic data might improve the prediction of possible disease outcome. A red tulip, a symbol of the disease, should make researchers and clinicians to consolidate their efforts in developing and refining therapies to conquer this devastating illness.

References

de Lau LM, & Breteler MM (2006). Epidemiology of Parkinson’s disease. Lancet neurology, 5 (6), 525-35 PMID: 16713924

Rascol O, Lozano A, Stern M, & Poewe W (2011). Milestones in Parkinson’s disease therapeutics. Movement disorders : official journal of the Movement Disorder Society, 26 (6), 1072-82 PMID: 21626552

Jenner P, Morris HR, Robbins TW, Goedert M, Hardy J, Ben-Shlomo Y, Bolam P, Burn D, Hindle JV, & Brooks D (2013). Parkinson’s disease–the debate on the clinical phenomenology, aetiology, pathology and pathogenesis. Journal of Parkinson’s disease, 3 (1), 1-11 PMID: 23938306

Goedert M, Spillantini MG, Del Tredici K, & Braak H (2013). 100 years of Lewy pathology. Nature reviews. Neurology, 9 (1), 13-24 PMID: 23183883

Wilhelmus MM, Nijland PG, Drukarch B, de Vries HE, & van Horssen J (2012). Involvement and interplay of Parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders. Free radical biology & medicine, 53 (4), 983-92 PMID: 22687462

Henchcliffe C, & Beal MF (2008). Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nature clinical practice. Neurology, 4 (11), 600-9 PMID: 18978800

Pankratz ND, Wojcieszek J, Foroud T. Parkinson Disease Overview. 2004 May 25 [updated 2009 Jul 09]. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.

Berardelli A, Wenning GK, Antonini A, Berg D, Bloem BR, Bonifati V, Brooks D, Burn DJ, Colosimo C, Fanciulli A, Ferreira J, Gasser T, Grandas F, Kanovsky P, Kostic V, Kulisevsky J, Oertel W, Poewe W, Reese JP, Relja M, Ruzicka E, Schrag A, Seppi K, Taba P, & Vidailhet M (2013). EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson’s disease. European journal of neurology : the official journal of the European Federation of Neurological Societies, 20 (1), 16-34 PMID: 23279440

Image via Wouter Tolenaars / Shutterstock.

Viatcheslav Wlassoff, PhD

Viatcheslav Wlassoff, PhD, is a scientific and medical consultant with experience in pharmaceutical and genetic research. He has an extensive publication history on various topics related to medical sciences. Dr. Wlassoff runs consulting service specialized on preparation of scientific publications, medical and scientific writing and editing.
See All Posts By The Author

Do not miss out ever again. Subscribe and get latest Brain Blogger articles straight to your inbox.