Mechanisms of Parkinson's Disease Linked to Pathological α-Synuclein: New Targets for Drug Discovery

Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, Maloney Building, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Neuron (Impact Factor: 15.05). 10/2006; 52(1):33-38. DOI: 10.1016/j.neuron.2006.09.026


Classic Parkinson's disease (PD) is characterized by fibrillar alpha-synuclein inclusions known as Lewy bodies in the substantia nigra, which are associated with nigrostriatal degeneration. However, alpha-synuclein pathologies accumulate throughout the CNS in areas that also undergo progressive neurodegeneration, leading to dementia and other behavioral impairments in addition to parkinsonism. Although mutations in the alpha-synuclein gene only cause Lewy body PD in rare families, and although there are multiple other, albeit rare, genetic causes of familial parkinsonism, sporadic Lewy body PD is the most common movement disorder, and insights into mechanisms underlying alpha-synuclein-mediated neurodegeneration provide novel targets for the discovery of disease-modifying therapies for PD and related neurodegenerative alpha-synucleinopathies.

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    • "Such mutations are considered gain-of-function, although it is often unclear which function is actually gained. Examples of genetic diseases caused by gain of poorly understood functions include α-synuclein-dependent familial Parkinson's disease and other synucleopathies (Lee and Trojanowski, 2006; Marques and Outeiro, 2012) or leucine-rich repeat kinase 2-dependent familial Parkinson's disease (Esteves et al., 2014). "
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    • "It was hypothesized that changes in aSyn phosphorylation could represent a response to biochemical events associated with PD pathogenesis. Among these, mitochondrial complex I dysfunction, oxidative stress and proteasome dysfunction are processes that are known to be involved in synucleinopathies (Lee and Trojanowski, 2006; Lashuel et al., 2013). Increased levels of pS129 aSyn were observed upon proteasome inhibition or oxidative stress in SH-SY5Y cells over-expressing aSyn. "
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    • "The formation of hyperphosphorylated Tau (microtubule-associated protein) in the neurons is also linked with AD. PD is a movement disorder which is characterized by abnormal aggregation of α-synuclein protein in the neurons [33]. Similarly, abnormal long polyglutamine (PolyQ) may lead to Huntington's disease [34]. "
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