TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression.
Marta Garcia-MontojoSaeed FathiCyrus RastegarElena Rita SimulaTara T Doucet-O'HareYong-Han Hank ChengRachel P M AbramsNicholas PasternackNasir MalikMuzna BachaniBrianna DisanzaDragan MaricMyoung-Hwa LeeHerui WangUlisses SantamariaWenxue LiKevon SampsonJuan Ramiro LorenzoIgnacio E SanchezAlexandre MezghraniYan LiLeonardo Antonio SechiSergio Sebastian PinedaMyriam HeimanManolis KellisJoseph SteinerAvindra NathPublished in: Nature communications (2024)
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.
Keyphrases
- amyotrophic lateral sclerosis
- binding protein
- poor prognosis
- endothelial cells
- cell proliferation
- spinal cord
- transcription factor
- resting state
- single molecule
- type diabetes
- single cell
- cerebral ischemia
- spinal cord injury
- multiple sclerosis
- long non coding rna
- functional connectivity
- metabolic syndrome
- south africa
- dna methylation
- adipose tissue
- cell cycle arrest
- signaling pathway
- molecular dynamics simulations
- blood brain barrier
- cell death
- insulin resistance
- nucleic acid
- circulating tumor cells
- protein protein