Paths to a cure for PD ?

USF Health - Movement Disorders Clinic, Byrd Institute














α-Synuclein in Parkinson’s disease: getting to the core of the matter



When patients ask me when we will have a cure for Parkinson’s disease, I still say that I don’t know. But unlike a few years ago, I now add that scientists have uncovered a major part of the disease process and we can now envision what a cure might look like and what  needs to be done to get there. I am referring to the fact that propagation of α-synuclein misfolding and aggregation seems to be at the heart of most types of Parkinson’s disease and that this process presents several attractive opportunities for therapeutic intervention, as reviewed by Dehay and colleagues.1


A role for α-synuclein in Parkinson’s disease was first suggested in 1997 by the identification of a mutation (Ala53Thr) in the α-synuclein gene in a subpedigree of a large Italian kindred and in three small Greek kindreds.2 Additional α-synuclein missense mutations, duplications, and triplications were subsequently described, but these are rare.3 Nonetheless, the demonstration that aggregated α-synuclein is the main component of Lewy bodies,4 even in patients without mutations in the α-synuclein gene, widely implicated α-synuclein as a central part of the disease process.

Our understanding of Parkinson’s disease was further advanced by the work of Braak and colleagues,5 who showed in post-mortem brains of patients with Parkinson’s disease a stereotypical topographical order of appearance of synuclein pathology.5 Pathology first appears in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and the anterior olfactory nucleus. The substantia nigra (midbrain) is affected subsequently, and the cortex is affected late, giving the impression of ascending involvement.

In 2008, two groups described the occurrence of Lewy body-like inclusions in neural grafts 11–16 years after implantation of embryonic neurons into the brains of patients with Parkinson’s disease.6,7 These observations suggested host-to-graft transmission of the disease and reframed the progression of pathology observed by Braak and colleagues as possible neuron-to-neuron transmission rather than simply differential susceptibility to a widespread process. Many preclinical studies have since suggested that α-synuclein can behave in a prion-like fashion, with misfolding and aggregation, and propagation from neuron to neuron by a templating process.8


This chain of events presents many  opportunities for therapeutic intervention.1

Therapies might be developed to reduce α-synuclein concentrations, α-synuclein misfolding or aggregation, or propagation from cell to cell. Upregulation of systems responsible for clearance of toxic aggregates or even inhibition of the toxic pathway(s) induced by aggregates might be possible; however, key questions remain. One of the most important of these is the question of which synuclein species are toxic and which might be protective. Because synuclein-targeting and other potential disease-modifying therapies are now rapidly being developed, we need ways to assess their effectiveness in patients and we need a pathway to regulatory approval.

Multiple system atrophy is a rapidly progressive neurodegenerative disorder marked by glial α-synucleinpositive inclusions. We certainly need a therapy to slow or stop its progression and α-synuclein-targeting therapies could be assessed in this population, bearing in mind that a particular therapy might be effective only in Parkinson’s disease or only in multiple system atrophy.

Trials of disease-modifying treatments for Parkinson’s disease could enroll patients with premotor disease. These studies could include individuals with hyposmia, rapid eye movement behaviour disorder, a genetic risk of Parkinson’s disease, or a suggestive electrophysiological test result, along with a positive imaging study such as a DatScan showing loss of dopaminergic neuron terminals. A population at such an early stage of disease might be more amenable to disease modification, and this approach could avoid the confounding effects of symptomatic therapy, which is typically needed within 1 year of a clinical diagnosis based on classic motor features. Participants could be followed for phenoconversion to a diagnosis of Parkinson’s disease and monitored with imaging to assess further loss of dopamine terminals or progression of other imaging biomarkers. Investigators are seeking to establish whether sufficient numbers of patients with premotor disease can be identified, and if a sufficient number of phenoconversions within a reasonable period of time.

We need to begin to push for the application of simple tests to be applied in the primary-care setting as first-round screens to identify individuals with possible premotor Parkinson’s disease. For now, this method would serve to identify individuals who might participate in clinical trials, but, hopefully in the future, we can also identify individuals who can benefit from disease-modifying therapy.

Substantial progress is being made in our efforts to provide patients with a robust symptomatic antiparkinsonian response through the day. New medications in development include longer-acting oral levodopa formulations and acute, intermittent therapies to treat “off ” episodes, such as inhaled levodopa and sublingual apomorphine. Additional options for patients with uncontrolled motor fluctuations include deep brain stimulation, levodopa-carbidopa intestinal infusion, and apomorphine or levodopa-carbidopa subcutaneous infusion.

By contrast, highly effective symptomatic therapies for disabling long-term features such as balance impairment and cognitive dysfunction seem beyond our grasp, which re-emphasises the need to slow and ultimately stop progression of this disease. Much work needs to be done, and we should not become overconfident or complacent. However, the on-going unravelling of the α-synuclein story allows me to tell patients that we appear to be on the cusp of seeing disease-modifying therapies emerge from preclinical work. Seems like we are on the right track.


Robert A Hauser

Departments of Neurology, Molecular Pharmacology and Physiology, University of South Florida Parkinson’s Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, Tampa, FL 33613, USA

Disclosure: I have received consultancy fees from Allergan Neuroscience, AbbVie, Auspex, Eli Lilly, Gerson Lehrman Group, Impax Laboratories, Michael J Fox Foundation, Teva, and UCB BioSciences; fees as a steering committee member for ChelseaTherapeutics and an advisory board member for Acadia, Acorda, AstraZeneca, Lundbeck, Neurocrine, and Pfizer; and speaker’s fees from Biotie, Novartis, Teva, and UCB Biosciences 



1 Dehay B, Bourdenx M, Gorry P, et al. Targeting α-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol 2015; published online June 3.

2 Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identifi ed in families with Parkinson’s disease. Science 1997; 276: 2045–47.

3 Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease. J Geriatr Psychiatry Neurol 2010; 23: 228–42.

4 Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature 1997; 388: 839–40.

5 Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24: 197–211.

6 Li JY et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 2008; 14: 501–03.

7 Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 2008; 14: 504–06.

8 Recasens A, Dehay B. Alpha-synuclein spreading in Parkinson’s disease. Front Neuroanat 2014; 8: 1–9.

9 Berg D, Marek K, Ross GW, Poewe W. Defi ning at-risk populations for Parkinson’s disease: lessons from ongoing studies. Mov Disord 2012; 27: 656–65.