We searched PubMed between Jan 1, 1993, to Feb 15, 2015 using the search terms “synuclein” or “alpha-synuclein” in combination with “Parkinson” or “Parkinson disease”, “protein aggregation”, “pathogenesis”, “pathologic hallmarks/features”, “pathologic mechanisms”, “neuroprotection”, “aetiology”, “molecular mechanisms”, “preclinical models”, “clinical trial”, “therapeutic”, and “clinical progression”. Articles were also identified through searches of the authors' own files. Additional articles
Personal ViewTargeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations
Introduction
During the past two decades, a myriad of studies have suggested a substantial pathogenic role for α-synuclein in both familial and sporadic Parkinson's disease. Parkinson's disease belongs to the family of synucleinopathies, which includes dementia with Lewy bodies and multiple system atrophy (MSA). Parkinson's disease is the second most common neurodegenerative disorder, affecting 1–3% of the population older than 50 years1 and more than 5 million people worldwide.2 Classic motor signs of Parkinson's disease—including bradykinesia, rigidity, resting tremor, and gait disturbance with postural instability3—can be attributed mainly to the substantial loss of dopamine-containing neurons in the substantia nigra pars compacta. In addition to dopaminergic cell loss, another pathological hallmark of Parkinson's disease is the presence of intraneuronal proteinaceous cytoplasmic inclusions, named Lewy bodies, and dystrophic Lewy neurites, both of which contain α-synuclein deposits. The mechanisms leading to the formation and the pathogenic significance of these inclusions remain unknown.
No neuroprotective or neurorestorative therapy exists for treatment of this chronic disorder. However, two key discoveries that were made 17 years ago have had a substantial effect on Parkinson's disease research: the identification of mutations in the gene encoding α-synuclein (SNCA) in families with Parkinson's disease4, 5 and the finding that α-synuclein is a major component of Lewy body pathology.4, 5 Despite increasing understanding of Parkinson's disease pathogenesis, the exact mechanisms of progressive dopaminergic cell loss in the substantia nigra pars compacta remain to be unravelled. In this Personal View, we review advances in understanding of the prominent role of α-synuclein in Parkinson's disease, outline major challenges in understanding the clinicopathological value of the several α-synuclein species, address how α-synuclein species could be used as disease biomarkers, and critically assess the potential of experimental therapies targeting α-synuclein. We conclude that therapeutic development should focus on this promising target.
Section snippets
α-Synuclein and Parkinson's disease
In 1912, Lewy6 first described the intraneuronal proteinaceous cytoplasmic inclusions that became the histopathological hallmark of Parkinson's disease, later referred to as “Lewy bodies” by Tretiakoff.7 In the early 1990s, α-synuclein was identified as the precursor of the non-amyloid component (NAC) of Alzheimer's disease amyloid plaques.8, 9, 10 The first link between α-synuclein and Parkinson's disease was made in 1997 with the identification of point mutations in the SNCA gene in familial
Focus on α-synuclein as a therapeutic target
α-Synuclein-related publications have consistently grown since its association with Parkinson's disease was discovered in 1997, to reach 552 articles published in 2014 alone (appendix); roughly 50% of these articles were published in the past 5 years (appendix). The increase in scientific publications has been associated with an increasing α-synuclein-related patent deposit rate (appendix). Since 1994, a total of 176 patent families have been filed, with an average of 20 patents per year in the
Strategies to combat α-synuclein toxicity
α-Synuclein aggregation is now regarded as a major pathogenic process in Parkinson's disease, and several strategies exist for prevention of α-synuclein toxicity.78 Although the evidence for these approaches is not conclusive enough yet, several clinical trials focusing on α-synuclein in Parkinson's disease have been initiated (table 1), and numerous additional approaches at the preclinical stage—often reflecting collaboration between industry and academia—are moving forward. Here we highlight
Conclusions and future directions
α-Synuclein has an unquestionable role in Parkinson's disease pathogenesis. Experimental research supports several therapeutic strategies to combat α-synuclein toxicity, with promising preclinical results. However, understanding of the clinicopathological association of various α-synuclein forms in patients with Parkinson's disease is just emerging and needs to be strengthened further. Additionally, we need to establish biomarkers of α-synuclein pathology in living patients and track their
Search strategy and selection criteria
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Authors contributed equally