Alpha Synuclein Aggregation in a Neurotoxic Model of Parkinson's Disease

Abstract

Abstract : The neurotoxin 1-methyl-4-phenyl-tetrahydropyridine (NPTP) inhibits mitochondrial oxidative phosphorylation and replicates the pattern of neuronal neurodegeneration found in Parkinson's disease (PD). Neurons that degenerate in PD develop inclusions containing a synaptic protein, alpha synuclein. We examined how MPTP and other neurotoxins affect cytoskeletal and synaptic proteins and studied the relationship between oxidative damage and synuclein aggregation in NPTP-treated mice. Oxidative injury is evident in dopaminergic neurons 4 days after toxin administration followed 3-6 days later by increased synuclein and ubiquitin immunoreactivity. Double staining studies show that oxidative markers are increased in neurons that develop increased alpha synuclein staining. Paraquat treatment causes nigral degeneration and alpha synuclein aggregation that is more prominent than that produced by MPTP. The proteasomal inhibitors lactacystin and epoxomicin protect mice form the neurotoxic effects of MPTP but may paradoxically increase alpha synuclein aggregation. Alpha synuclein knockout mice resist the neurotoxic effects of MPTP and other mitochondrial toxins including malonate, 3-nitropropionic acid and paraquat. Our studies show that MPTP-induced oxidative injury precedes increased neuronal alpha synuclein staining and suggest that alpha synuclein and abnormal proteasomal function could contribute to neurotoxin and PD-related neuronal cell death. Reducing synuclein expression may be a novel approach to the treatment of PD.