Part II: α-synuclein and its molecular pathophysiological role in neurodegenerative disease

Dev, Kumlesh K., Hofele, Katja, Barbieri, Samuel, Buchman, Vladmir L. ORCID: https://orcid.org/0000-0002-7631-8352 and van der Putten, Herman 2003. Part II: α-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology 45 (1) , pp. 14-44. 10.1016/S0028-3908(03)00140-0

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Abstract

α-Synuclein (αSN) brain pathology is a conspicuous feature of several neurodegenerative diseases. These include prevalent conditions such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and the Lewy body variant of Alzheimer’s disease (LBVAD), as well as rarer conditions including multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). Common in these diseases, some referred to as α-synucleinopathies, are microscopic proteinaceous insoluble inclusions in neurons and glia that are composed largely of fibrillar aggregates of αSN. This molecular form of αSN contrasts sharply with normal αSN, which is an abundant soluble presynaptic protein in brain neurons. αSN is a highly conserved protein in vertebrates and only seven of its 140 amino acids differ between human and mouse. Flies lack an αSN gene. Implicated in neurotoxicity are two αSN mutants (A53T and A30P) that cause extremely rare familial forms of PD, αSN fibrils and protofibrils, soluble protein complexes of αSN with 14-3-3 protein, and phosphorylated, nitrosylated, and ubiquitylated αSN species. Unlike rare forms of fPD caused by mutations in αSN, disease mechanisms in most α-synucleinopathies implicate wildtype αSN and seem to converge around oxidative damage and impairments in protein catabolism. It is not known whether these causalities involve αSN from the beginning, but defects in the handling of this protein seem to contribute to disease progression because accumulation of toxic αSN forms damage neurons. Here, we summarize the main structural features of αSN and its functions, and discuss the molecular αSN species implicated in human disease and transgenic animal models of α-synucleinopathy in fly and rodents.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Uncontrolled Keywords:	α-Synuclein; α-Synucleinopathies; Lewy bodies; Neurodegeneration; Parkinson’s disease; Alzheimer’s disease.
Publisher:	Elsevier
ISSN:	0028-3908
Last Modified:	27 Oct 2022 08:45
URI:	https://orca.cardiff.ac.uk/id/eprint/63288

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