Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

Appoptosin Mediates Lesions Induced by Oxidative Stress Through the JNK-FoxO1 Pathway.

Oxidative stress is a common feature of neurodegenerative diseases and plays an important role in disease progression. Appoptosin is a pro-apoptotic protein that contributes to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. However, whether appoptosin mediates oxidative stress-induced neurotoxicity has yet to be determined. Here, we observe that appoptosin protein levels are induced by hydrogen peroxide (H2O2) exposure through the inhibition of proteasomal appoptosin degradation. Furthermore, we demonstrate that overexpression of appoptosin induces apoptosis through the JNK-FoxO1 pathway. Importantly, knockdown of appoptosin can ameliorate H2O2-induced JNK activation and apoptosis in primary neurons. Thus, we propose that appoptosin functions as an upstream regulator of the JNK-FoxO1 pathway, contributing to cell death in response to oxidative stress during neurodegeneration.

Intracellular trafficking of TREM2 is regulated by presenilin 1.

Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to a variety of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinson's disease. In the brain, TREM2 is highly expressed on the cell surface of microglia, where it can transduce signals to regulate microglial functions such as phagocytosis. To date, mechanisms underlying intracellular trafficking of TREM2 remain elusive. Mutations in the presenilin 1 (PS1) catalytic subunit of the γ-secretase complex have been associated with increased generation of the amyloidogenic Aß (amyloid-ß) 42 peptide through cleavage of the Aß precursor amyloid precursor protein. Here we found that TREM2 interacts with PS1 in a manner independent of γ-secretase activity. Mutations in TREM2 alter its subcellular localization and affects its interaction with PS1. Upregulation of PS1 reduces, whereas downregulation of PS1 increases, steady-state levels of cell surface TREM2. Furthermore, PS1 overexpression results in attenuated phagocytic uptake of Aß by microglia, which is reversed by TREM2 overexpression. Our data indicate a novel role for PS1 in regulating TREM2 intracellular trafficking and pathophysiological function.