Lysosomal Ca2+ disruption induces autophagy impairment in familial Alzheimer’s disease

Abstract

Autophagy is an evolutionary conserved cellular pathway for the cell to cope with stress and starvation. Deranged autophagy has been observed in Alzheimer’s disease (AD)[1] and it has been reported that presenilin-1(PS1) is essential for the maintenance of acidic lysosomal pH[2]. However, the underlying molecular mechanism for lysosomal alkalization due to PS1 mutation is still obscure. Two-pore channel 2 (TPC2) is a lysosomal Ca2+ release channel that was found to play a role in lysosomal alkalization[3]. Here we found that PS1 interacted with TPC2 channel in the human neuroblastoma SH-SY5Y. The lysosomal Ca2+ content was significantly lower while its pH was higher in PS1-M146L expressing SH-SY5Y than those of wild-type PS1 expressing cell and GFP-expressing control cell. Intriguingly, reduced lysosomal Ca2+ content and alkalization in PS1-M146L can be rescued by treating the cell with TPC2 specific inhibitor, NED-19. Consistent Ca2+ disruption and lysosomal alkalization were observed in fibroblasts isolated from AD patients with PS1 mutation and these derangements were corrected by NED-19. Together, our results suggested that lysosomal Ca2+ disruption due to PS1 mutation plays a role in the pathogenic mechanism for autophagy impairment in familial AD and this provided a novel target for therapeutic intervention of the disease.