Progress for Parkinson’s

In PD, the TOM40 protein, a key component of the outer mitochondrial membrane (OMM), is linked to α-synuclein (α-Syn) pathology, and Hegde’s team discovered that TOM40 protein depletion occurs in the brains of patients with Guam PD as well as in cultured neurons expressing α-Syn proteinopathy; a depletion that occurs without corresponding changes in TOM40 mRNA levels. The study reveals that aggregates of α-synuclein can damage neuronal mitochondria by breaking down their TOM40, impacting mitochondrial function and leading to problems with energy production related to Guam PD. Their comprehensive analyses demonstrate that mutant α-Syn-induced loss of TOM40 results in reduced mitochondrial membrane potential, accumulation of mtDNA damage, deletion and insertion mutations, and altered oxygen consumption rates. Importantly, they also show that ectopic supplementation of TOM40 or reducing pathological forms of α-Syn ameliorated these mitochondrial defects, suggesting potential therapeutic avenues.