TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
Marta García‐Montojo, Saeed Fathi, Cyrus Rastegar, Elena Rita Simula, Tara T. Doucet-O’Hare, Yong-Han Hank Cheng, Rachel P. M. Abrams, Nicholas Pasternack, Nasir Malik, Muzna Bachani, Brianna Disanza, Dragan Maric, Myoung‐Hwa Lee, Herui Wang, Ulisses A. Santamaria, Wenxue Li, Kevon Sampson, Ramiro Lorenzo, Ignacio E. Sánchez, Alexandre Mezghrani, Yan Li, Leonardo A. Sechi, S. Sebastian Pineda, Myriam Heiman, Manolis Kellis, Joseph Steiner, Avindra Nath
Abstract
TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.