TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression

Marta Garcia-Montojo, Saeed Fathi, Cyrus Rastegar, Elena Rita Simula, Tara Doucet-O’Hare, Y. H. Hank Cheng, Rachel P. M. Abrams, Nicholas Pasternack, Nasir Malik, Muzna Bachani, Brianna Disanza, Dragan Maric, Myoung-Hwa Lee, Herui Wang, Ulisses Santamaria, Wenxue Li, Kevon Sampson, Juan Ramiro Lorenzo, Ignacio E. Sanchez, Alexandre Mezghrani, Yan Li, Leonardo Antonio Sechi, Sebastian Pineda, Myriam Heiman, Manolis Kellis, Joseph Steiner and Avindra Nath ()
Additional contact information
Marta Garcia-Montojo: National Institutes of Health (NIH)
Saeed Fathi: National Institutes of Health (NIH)
Cyrus Rastegar: National Institutes of Health (NIH)
Elena Rita Simula: National Institutes of Health (NIH)
Tara Doucet-O’Hare: National Institutes of Health (NIH)
Y. H. Hank Cheng: National Institutes of Health (NIH)
Rachel P. M. Abrams: National Institutes of Health (NIH)
Nicholas Pasternack: National Institutes of Health (NIH)
Nasir Malik: National Institutes of Health (NIH)
Muzna Bachani: National Institutes of Health (NIH)
Brianna Disanza: National Institutes of Health (NIH)
Dragan Maric: National Institutes of Health (NIH)
Myoung-Hwa Lee: National Institutes of Health (NIH)
Herui Wang: National Cancer Institute (NIH)
Ulisses Santamaria: National Institutes of Health (NIH)
Wenxue Li: National Institutes of Health (NIH)
Kevon Sampson: National Institutes of Health (NIH)
Juan Ramiro Lorenzo: Universidad Nacional del Centro (FCV-UNCPBA)
Ignacio E. Sanchez: Universidad de Buenos Aires
Alexandre Mezghrani: National Institutes of Health (NIH)
Yan Li: National Institutes of Health (NIH)
Leonardo Antonio Sechi: Azienda Ospedaliera Universitaria Sassari
Sebastian Pineda: Massachusetts Institute of Technology
Myriam Heiman: Massachusetts Institute of Technology
Manolis Kellis: Massachusetts Institute of Technology
Joseph Steiner: National Institutes of Health (NIH)
Avindra Nath: National Institutes of Health (NIH)

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48488-7

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