Abstract
BackgroundAlpha-synuclein is a key protein in the pathogenesis of Parkinson’s disease. Mutations in the parkin gene are the most common cause of early-onset autosomal recessive Parkinson’s disease, probably through a loss-of-function mechanism. However, the molecular mechanism by which loss of parkin function leads to the development of the disease and the role of alpha-synuclein in parkin-associated Parkinson’s disease is still not elucidated. Conflicting results were reported about the effect of the absence of parkin on alpha-synuclein-mediated neurotoxicity using a transgenic approach. In this study, we investigated the effect of loss of parkin on alpha-synuclein neuropathology and toxicity in adult rodent brain using viral vectors. Therefore, we overexpressed human wild type alpha-synuclein in the substantia nigra of parkin knockout and wild type mice using two different doses of recombinant adeno-associated viral vectors.ResultsNo difference was observed in nigral dopaminergic cell loss between the parkin knockout mice and wild type mice up to 16 weeks after viral vector injection. However, the level of alpha-synuclein phosphorylated at serine residue 129 in the substantia nigra was significantly increased in the parkin knockout mice compared to the wild type mice while the total expression level of alpha-synuclein was similar in both groups. The increased alpha-synuclein phosphorylation was confirmed in a parkin knockdown cell line.ConclusionsThese findings support a functional relationship between parkin and alpha-synuclein phosphorylation in rodent brain.
Highlights
Alpha-synuclein is a key protein in the pathogenesis of Parkinson’s disease
Absence of parkin does not increase the sensitivity to dopaminergic degeneration induced by a high dose of rAAV2/7-wild type (WT) α-SYN In a previous study, we showed that rAAV2/7-mediated overexpression of WT α-SYN in the substantia nigra (SN) of mice resulted in a dose-dependent, progressive dopaminergic neurodegeneration [33]
At 4 weeks after injection, the rAAV2/7-WT α-SYN induced a dopaminergic lesion of 59 ± 6% compared to the non-injected side in the parkin +/+ mice, which is in agreement with our previous study [33] (Figure 1 and 3A)
Summary
Alpha-synuclein is a key protein in the pathogenesis of Parkinson’s disease. Mutations in the parkin gene are the most common cause of early-onset autosomal recessive Parkinson’s disease, probably through a loss-of-function mechanism. Parkinson’s disease (PD) is the second most common neurodegenerative disorder It is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and the presence of proteinaceous intracellular inclusions called Lewy bodies (LBs) and Lewy neurites in the surviving neurons [1]. Rompuy et al Molecular Neurodegeneration (2015) 10:23 conditions, including mutations and increased expression levels, α-SYN has the propensity to adopt a β-sheet rich conformation which leads to the formation of oligomers and fibrillar aggregates [8]. This fibrillar form of α-SYN is the main protein component of LBs and Lewy neurites, indicating that α-SYN plays a crucial role in the pathogenesis of PD [9]. Animal models based on overexpression of wild type (WT) or mutant α-SYN, recapitulate some of the main hallmarks of PD, including neurodegeneration, motor dysfunction and inclusion formation [10]
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