Nigral overexpression of alpha-synuclein in the absence of parkin enhances alpha-synuclein phosphorylation but does not modulate dopaminergic neurodegeneration

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.

How can rAAV‐α‐synuclein and the fibril α‐synuclein models advance our understanding of Parkinson's disease?

“…However, in the absence of parkin in mice does not exacerbate α‐synuclein over‐expression‐induced neuron death (Van Rompuy et al . ). Thus, the relationship between α‐synuclein in parkin requires further investigation.…”

“…Viral-induced co-expression of Parkin and a-synuclein in the substantia nigra reduces the extent of neuron loss produced by expression of a-synuclein alone (Lo Bianco et al 2004;Yamada et al 2005). However, in the absence of parkin in mice does not exacerbate a-synuclein over-expression-induced neuron death (Van Rompuy et al 2015). Thus, the relationship between a-synuclein in parkin requires further investigation.…”

Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease

“…Fifteen studies published from 2002 to 2019 have investigated how either parkin depletion or overexpression affects -synuclein toxicity. Of the fifteen studies, eleven showed a functional interaction between parkin and -synuclein [ 182 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 ], and four studies did not [ 227 , 228 , 229 , 230 ]. An in vitro study by Petrucelli et al in 2002 investigated whether parkin overexpression would be neuroprotective in a primary cell culture overexpressing mutated -synuclein [ 217 ].…”

α-synuclein expression from a single copy transgene increases sensitivity to stress and accelerates neuronal loss in genetic models of Parkinson's disease

“…Increasing parkin expression using a lentiviral delivery system in rats decreased the levels of phosphorylated α-synuclein and prevented levels of inflammation and cell death compared to expressing α-synuclein alone (Khandelwal et al, 2010). Similarly, knocking out parkin expression in mice resulted in increased levels of phosphorylated α-synuclein (Van Rompuy et al, 2015). Further work has shown that the mechanism by which parkin affects the levels of α-synuclein is by modulating α-synuclein degradation (Lonskaya et al, 2013).…”