Metabolic dysfunction and protein aggregation are associated with neurodegenerative disorders such as Alzheimer's disease (AD). However, the mechanisms underlying these abnormalities remain poorly understood. Mutations in the presenilin encoding genes are the primary cause of early onset familial AD, but their role in the disease is unclear. The presenilins are primarily known to function as the catalytic component of the gamma-secretase complex, which is involved in the cleavage of the amyloid precursor protein (APP) to produce amyloid beta (Abeta) peptides, whose aggregation into Abeta plaques is considered the hallmark of AD. However, many studies have demonstrated a gamma-secretase independent role for presenilins in calcium homeostasis that is critical for neuronal health. Previously, we showed that loss of the Caenorhabditis elegans presenilin ortholog SEL-12 elevates mitochondrial calcium signaling, which increases mitochondrial metabolism to drive neurodegeneration and loss of protein homeostasis. Here, we demonstrate that this elevated mitochondrial calcium and concomitant mitochondrial hyperactivity promotes activation of the mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway. We utilize several models of protein homeostasis to show mTORC1 hyperactivity contributes to protein homeostasis defects. Reducing mTORC1 activity improves neurodegenerative phenotypes associated with loss of SEL-12/presenilin function. We also show mTORC1 plays a cell-autonomous role in neurodegeneration and that rescue of neuronal mTORC1 signaling is sufficient to abrogate improvements to neuronal function caused by global mTORC1 inhibition. Consistent with high mTORC1 activity, we find that SEL-12/presenilin loss reduces autophagy, and this reduction is prevented by limiting mitochondrial calcium uptake. Furthermore, the improvements to protein homeostasis and neuronal function in
sel-12 mutants due to mTORC1 inhibition require the induction of autophagy. Collectively, these results indicate that mTORC1 hyperactivation exacerbates the defects in protein homeostasis, autophagy, and neuronal function in
sel-12 mutants and suggest a potential therapeutic target for treating AD.