“Altogether, our data suggests a link between a-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism,” wrote the scientists.
Inclusions of a-synuclein in the brain distinguish Parkinson’s from other diseases. To gain insight into the cellular processes that play a role in the misfolding of this protein, the group looked for genes in C. elegans that if switched off, cause the number of inclusions to increase. During the course of their research, the scientists individually switched off 17,000 of the 19,000 genes.
From RNAi screening, the researchers discovered 80 genes that when inhibited, increased inclusion formation. A large proportion of these genes are involved in quality control and vesicle-trafficking in the ER/Golgi complex and vesicular compartments. Aging-associated genes such as sir-2.1 (SIRT1 in humans) and lagr-1 (LASS2) were also found to have an effect on inclusion formation.
The researchers involved were from the University Medical Centre Groningen, University of Groningen, and Netherlands Institute of Developmental Biology. The findings are described in an article published on March 21 in PLoS Genetics.