Parkinson's disease (PD) is a progressive neurodegenerative movement disorder which is caused by a selective loss of dopaminergic neurons in the substantia nigra (SNc). One of the pathological hallmarks of PD is the presence of Lewy bodies (LBs) in the affected neurons. A major component of Lewy bodies is alpha-synuclein (α-syn), and it is believed that misfolded and abnormal accumulation of α-syn is directly linked to the pathogenesis of PD. α-syn is the first gene that was identified in relation to familial PD and it has been proposed that oxidative stress or mutations can enhance the aggregation of α-syn, which can cause the degeneration of dopaminergic neurons in the SNc. To test this hypothesis, a short peptide called CL1 was attached at the C-terminal of α-syn which promotes its t...[ Read more ]

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder which is caused by a selective loss of dopaminergic neurons in the substantia nigra (SNc). One of the pathological hallmarks of PD is the presence of Lewy bodies (LBs) in the affected neurons. A major component of Lewy bodies is alpha-synuclein (α-syn), and it is believed that misfolded and abnormal accumulation of α-syn is directly linked to the pathogenesis of PD. α-syn is the first gene that was identified in relation to familial PD and it has been proposed that oxidative stress or mutations can enhance the aggregation of α-syn, which can cause the degeneration of dopaminergic neurons in the SNc. To test this hypothesis, a short peptide called CL1 was attached at the C-terminal of α-syn which promotes its tendency to aggregate. Results suggest that promoting α-syn aggregation can enhance its toxicity. CL1 induces α-syn aggregate formation in vitro and in cultured cells that contributes to the increase in cytotoxicity. CL1 fused WT and mutant α-syn have high sensitivity to oxidative stress, proteasome inhibitor Congo red and HSP70. LBs-like inclusions can be detected in cells and neurons expressing CL1 fused α-syn. Adenovirus transduced mice show that CL1 enhances α-syn induced dopaminergic neuron degeneration in a time-dependent manner. LBs like inclusions also can be detected in affected mouse neurons. I propose that α-syn aggregation causes cytotoxicity and triggers neurodegeneration in cells and in my animal model.