Perspective: Low Risk of Parkinson's Disease in Quasi-Vegan Cultures May Reflect GCN2-Mediated Upregulation of Parkin

Abstract

ABSTRACT Mitochondrial dysfunction in dopaminergic neurons of the substantia nigra (SN) appears to be a key mediating feature of Parkinson's disease (PD), a complex neurodegenerative disorder of still unknown etiology. Parkin is an E3 ubiquitin ligase that promotes mitophagy of damaged depolarized mitochondria while also boosting mitochondrial biogenesis—thereby helping to maintain efficient mitochondrial function. Boosting Parkin expression in the SN with viral vectors is protective in multiple rodent models of PD. Conversely, homozygosity for inactivating mutations of Parkin results in early-onset PD. Moderate protein plant-based diets relatively low in certain essential amino acids have the potential to boost Parkin expression by activating the kinase GCN2, which in turn boosts the expression of ATF4, a factor that drives transcription of the Parkin gene. Protein-restricted diets also upregulate the expression of PINK1, a protein that binds to the outer membrane of depolarized mitochondria and then recruits and activates Parkin. This effect of protein restriction is mediated by the downregulation of the kinase activity of mammalian target of rapamycin complex 1; the latter suppresses PINK1 expression at the transcriptional level. During the 20th century, cultures in East Asia and sub-Sahara Africa consuming quasi-vegan diets were found to be at notably decreased risk of PD compared with the USA or Europe. It is proposed that such diets may provide protection from PD by boosting Parkin and PINK1 expression in the SN. Other measures that might be expected to upregulate protective mitophagy include supplemental N-acetylcysteine (precursor for hydrogen sulfide) and a diet rich in spermidine—a polyamine notably high in corn.