Abstract
Protein homeostasis and lipid metabolism are essential processes frequently disrupted in neurodegenerative diseases. However, their mechanistic intersection in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to ALS/FTD. Through multi-omic analyses of induced pluripotent stem cell (iPSC)-derived neurons harboring disease-associated UBQLN2 mutations, we uncovered UBQLN2 as a molecular hub linking lipid dysregulation and proteostasis, the perturbation of which contributes to neurodegeneration. UBQLN2 mediated the degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase 3 family member A2), two enzymes essential for mitochondrial lipid catabolism associated with lipid droplets and neuronal viability. ALS/FTD-linked UBQLN2 mutations and TAR DNA-binding protein 43 (TDP-43) pathology impair the degradation of ILVBL and ALDH3A2, leading to metabolic dysfunction and neurodegeneration. Restoring the UBQLN2-ILVBL/ALDH3A2 axis attenuates neurodegenerative phenotypes in neurons, organoids and mice, establishing UBQLN2 as a critical regulator of metabolic homeostasis in ALS/FTD and other related neurodegenerative diseases.