Alpha Synuclein: Inhibitors
Drug-induced inhibition of α-synuclein aggregation and fibrilization
A common area of research in PD therapy is the development of drugs targeting fibril growth to inhibit α-synuclein induced toxicity. Mahul-Mellier et al. (2015)., showed that Tolcapone, a fibrilization inhibitor, and the replacement of α-synuclein with β-synuclein halts α-synuclein toxicity in both neuroblastoma cell lines and hippocampal primary neurons. β-synuclein lacks the NAC region (non Aβ component), therefore, does not form fibrils.
Rho-associated protein kinase (ROCK) is part of the α-synuclein aggregation pathway and was labelled as a “novel neuroprotectant target” in PD research. Tatenhorst et al. (2016) showed that a ROCK inhibitor, Fasudil, considerably lowered α-synuclein aggregation in an H4 cell culture model and a cell-free assay. Fasudil not only inhibits ROCK activation, but directly interacts with α-synuclein residues Y133 and Y136 in the C terminal region. Ultimately, improved motor and cognitive functions were observed in α-SynA53T mice who received Fasudil.
Deteriorated mitochondrial function is often correlated with PD pathogenicity; Lee et al. (2002), explored the effect of mitochondrial electron-transport chain inhibitors on α-synuclein aggregation. Administration of both rotenone (complex I inhibitor) and oligomycin (ETC inhibitor) resulted in increased α-synuclein aggregation. Therefore, α-synuclein inclusions could be caused by impaired mitochondrial activity and reversed with the recovery of mitochondrial function.