Role of alzheimer’s disease presenilin-1 associated protein in mitochondrial apoptosis

The process of apoptosis, a programmed form of cell death, is a normal occurrence during neurogenesis in the maturation of the central nervous system. However, dysregulated or premature activation of apoptosis can contribute to the pathogenesis of various neurodegenerative disorders. Indeed, studies have implicated that apoptosis plays a pivotal role in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). Early studies have demonstrated the involvement of both presenilin-1 (PS1) and Presenilin-2 (PS2), proteins associated with Alzheimer’s disease, in apoptosis. However, the exact mechanism is unknown. In an attempt to investigate the pathogenic function of PS1, using the yeast-two hybrid system, our study identified a novel PS-1-associated protein (PSAP). Subsequently, our studies revealed that PSAP functions as a proapoptotic molecule localized in mitochondria[1, 2]. This discovery establishes a direct molecular connection between PS1 and the apoptotic pathway, thereby paving the way for further exploration into the molecular mechanisms underlying PS-1-mediated apoptosis.

In a subsequent study, utilizing siRNA and knockout cell methodologies, we unveiled that PS1-induced apoptosis is dependent on mitochondria and primarily mediated by PSAP. Furthermore, to further elucidate the mechanism underlying PSAP-mediated apoptosis, our investigations demonstrated that PSAP triggers a distinct mitochondrial apoptotic pathway that operates independently of regulation by Bcl-2 family proteins. The apoptotic cascades leading to PSAP-mediated mitochondrial apoptosis were further investigated through a subsequent round of yeast-two hybrid system screening, revealing an interaction between PSAP and the death receptor DR6. Interestingly, PSAP is absolutely required for DR6-induced apoptosis in mediating DR6-induced Bax translocation of DR6 from cytosol to mitochondria. These results suggest PSAP may function as an anchor of Bax on the mitochondria. These novel observations might be exploited to develop a novel drug approach to manage AD.