Academic Journal
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
| العنوان: | TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression |
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| المؤلفون: | 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, Avindra Nath |
| المصدر: | Nature Communications, Vol 15, Iss 1, Pp 1-24 (2024) |
| بيانات النشر: | Nature Portfolio |
| سنة النشر: | 2024 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Science |
| الوصف: | 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. ASRGL 1 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2041-1723 |
| Relation: | https://doi.org/10.1038/s41467-024-48488-7; https://doaj.org/toc/2041-1723; https://doaj.org/article/3f8582a67a364758825325a7f9cb9801 |
| DOI: | 10.1038/s41467-024-48488-7 |
| الاتاحة: | https://doi.org/10.1038/s41467-024-48488-7 https://doaj.org/article/3f8582a67a364758825325a7f9cb9801 |
| رقم الانضمام: | edsbas.F672BDE8 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 20411723 |
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| DOI: | 10.1038/s41467-024-48488-7 |