Autophagy at the Crossroads of Protein and RNA Toxicity in Repeat Expansion Cerebellar Ataxias.

Cells maintain accurate translation to ensure proper protein synthesis. Canonical translation initiates when the small (40S) ribosomal subunit scans the mRNA to recognize the AUG start codon, followed by the joining of the large (60S) subunit [,]. During this process, co-translational mRNA decay serves as an indispensable quality control mechanism that safeguards cellular protein homeostasis (proteostasis) [,,]. Aberrant mRNAs, such as those lacking stop codons, harboring premature termination codons, or containing stable secondary structures, can induce ribosome stalling and activate specialized mRNA surveillance pathways, including nonsense-mediated decay (NMD), non-stop decay (NSD), and no-go decay (NGD) [,]. This surveillance is particularly critical in post-mitotic neurons due to their heightened sensitivity to proteotoxic stress. Consequently, dysregulation of co-translational decay and ribosome stalling resolution is increasingly implicated as a core driver of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [,,,,]. Failure to efficiently eliminate aberrant mRNAs and stalled ribosome complexes results in the accumulation of neurotoxic proteins and misfolded aggregates [,]. While eukaryotic mRNA translation typically begins at the AUG start codon on transcripts bearing a 5′ cap structure, nucleotide repeat expansions, which cause more than 50 neurological diseases, can drive translation in the absence of AUG start codons via both cap-dependent and cap-independent mechanisms [,,,,]. This phenomenon, termed repeat-associated non-AUG (RAN) translation, is exemplified by the GGGGCC hexanucleotide repeat expansion (HRE) in , the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [,]. RAN translation occurs in all three reading frames of C9-HRE, generating three dipeptide repeat (DPR) proteins: poly-GA, poly-GP, and poly-GR. These DPRs are highly neurotoxic, and their accumulation is a pathological hallmark of C9-ALS/FTD [,,,,]. Moreover, DPR expression alone is sufficient to recapitulate ALS/FTD pathological and behavioral phenotypes in multiple in vivo models [,,,,,]. Consistently, suppression of RAN translation using gene editing, without altering the C9-HRE sequence or expression levels, fully rescues motor and cognitive behavioral defects in mice []. Thus, RAN translation activity dictates DPR production and drives the subsequent pathogenesis of C9-ALS/FTD. Recent studies have shown that RAN translation induces ribosome stalling, partly due to stable RNA secondary structures and electrostatic interactions between positively charged arginine residues in poly-GR/poly-GP and the ribosomal exit tunnel [,,]. Moreover, multiple ribosomal quality control factors, including ZNF598, NEMF, LTN1, and ANKZF1, promote the degradation of nascent DPR chains [,,,,]. Consequently, the depletion of these factors exacerbates RAN product accumulation, indicating that aberrant RAN translation is subject to active surveillance mechanisms that limit DPR production and mitigate disease progression. However, the mechanisms by which C9-HRE-containing mRNAs are monitored during RAN translation remain largely unknown.