Staufen Impairs Autophagy in Neurodegeneration

Abstract

Objective The mechanistic target of rapamycin (mTOR) kinase is one of the master coordinators of cellular stress responses, regulating metabolism, autophagy, and apoptosis. We recently reported that staufen1 (STAU1), a stress granule (SG) protein, was overabundant in fibroblast cell lines from patients with spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis, frontotemporal degeneration, Huntington's, Alzheimer's, and Parkinson's diseases as well as animal models, and patient tissues. STAU1 overabundance is associated with mTOR hyperactivation and links SG formation with autophagy. Our objective was to determine the mechanism of mTOR regulation by STAU1. Methods We determined STAU1 abundance with disease‐ and chemical‐induced cellular stressors in patient cells and animal models. We also used RNA‐binding assays to contextualize STAU1 interaction with MTOR mRNA. Results STAU1 and mTOR were overabundant in bacterial artificial chromosome (BAC)‐C9ORF72, ATXN2Q127, and Thy1‐TDP‐43 transgenic mouse models. Reducing STAU1 levels in these mice normalized mTOR levels and activity and autophagy‐related marker proteins. We also saw increased STAU1 levels in HEK293 cells transfected to express C9ORF72‐relevant dipeptide repeats (DPRs). Conversely, DPR accumulations were not observed in cells treated by STAU1 RNA interference (RNAi). Overexpression of STAU1 in HEK293 cells increased mTOR levels through direct MTOR mRNA interaction, activating downstream targets and impairing autophagic flux. Targeting mTOR by rapamycin or RNAi normalized STAU1 abundance in an SCA2 cellular model. Interpretation STAU1 interaction with mTOR drives its hyperactivation and inhibits autophagic flux in multiple models of neurodegeneration. Staufen, therefore, constitutes a novel target to modulate mTOR activity and autophagy, and for the treatment of neurodegenerative diseases. ANN NEUROL 2023;93:398–416

Targeting Staufen 1 with antisense oligonucleotides for treating ALS and SCA2

“…16.516816 doi: bioRxiv preprint neurodegenerative diseases, including in the relevant cellular and transgenic mouse models and human patient tissues and cultured fibroblast cells. In addition to SCA2 these include Huntington's disease (HD), C9orf72 ALS, and TDP-43 ALS (1,3,4). STAU1 overabundance is associated with abnormal autophagy in multiple human tissues and mouse models of neurodegenerative disease (1,3,4).…”

“…In addition to SCA2 these include Huntington's disease (HD), C9orf72 ALS, and TDP-43 ALS (1,3,4). STAU1 overabundance is associated with abnormal autophagy in multiple human tissues and mouse models of neurodegenerative disease (1,3,4). Mechanistically, this occurs by STAU1 direct interaction with the MTOR mRNA 5'-UTR resulting in its increased translation (4).…”

“…We found that STAU1 is overabundant in SCA2 and other neurodegenerative diseases, including in the relevant cellular and transgenic mouse models and human patient tissues and cultured fibroblast cells. In addition to SCA2 these include Huntington’s disease (HD), C9orf72 ALS, and TDP-43 ALS (1,3,4).…”

“…STAU1 overabundance is associated with abnormal autophagy in multiple human tissues and mouse models of neurodegenerative disease (1,3,4). Mechanistically, this occurs by STAU1 direct interaction with the MTOR mRNA 5’-UTR resulting in its increased translation (4). Reducing STAU1 abundance normalized autophagy marker proteins in various systems including HEK-293 cells edited to express polyglutamine expanded ATXN2-Q58, and cultured patient fibroblasts from SCA2, TDP-43 and C9orf72 ALS patients, and transgenic mouse models with TDP-43 or C9orf72 mutations (3,4).…”

“…Mechanistically, this occurs by STAU1 direct interaction with the MTOR mRNA 5’-UTR resulting in its increased translation (4). Reducing STAU1 abundance normalized autophagy marker proteins in various systems including HEK-293 cells edited to express polyglutamine expanded ATXN2-Q58, and cultured patient fibroblasts from SCA2, TDP-43 and C9orf72 ALS patients, and transgenic mouse models with TDP-43 or C9orf72 mutations (3,4). Additionally, lowering Staufen abundance improves SCA2 mouse motor phenotypes and protein aggregations and mTOR-related autophagy phenotypes (1,3,4).…”