Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein

Abstract

Parkinson's disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded alpha-synuclein in selected brain regions, including the substantia nigra pars compacta (SNpc), where marked loss of dopaminergic neurons is also observed. Yet, the relationship between misfolded alpha-synuclein and neurotoxicity currently remains unclear. As the principal route for degradation of misfolded proteins in mammalian cells, the ubiquitin-proteasome system (UPS) is critical for maintenance of cellular proteostasis. Misfolded alpha-synuclein impairs UPS function and contributes to neuronal death in vitro. Here, we examine its effects in vivo using adeno-associated viruses to co-express A53T alpha-synuclein and the ubiquitinated reporter protein Ub(G76V)-GFP in rat SNpc. We found that alpha-synuclein over-expression leads to early-onset catalytic impairment of the 26S proteasome with associated UPS dysfunction, preceding the onset of behavioural deficits and dopaminergic neurodegeneration. UPS failure in dopaminergic neurons was also associated with selective accumulation of alpha-synuclein phosphorylated at the serine 129 residue, which has previously been linked to increased neurotoxicity. Our study highlights a role for alpha-synuclein in disturbing proteostasis which may contribute to neurodegeneration in vivo.