phos-Maintenance of chaperone‑mediated autophagy activity in cultured cells expressing mutant huntingtin

Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease.

A previously unrecognized modulatory role of wt-C9orf72 in regulating mHTT aggregation in experimental HD models is identified and a novel wt-C9orf72-Stat1-Isg15 axis is identified, providing new insights into wt-C9orf72-associated protein homeostasis.

LAMP2A-dependent chaperone mediated autophagy regulates Notch signaling and controls neural stem cell differentiation.

Protein degradation systems have profound effects on signaling pathways and molecular networks that regulate organogenesis. Chaperone Mediated Autophagy (CMA) has been linked to neurodegenerative and neurodevelopmental diseases, however, its role in mammalian brain development remains poorly understood. Here, we identify a regulatory role of CMA pathway in neural stem cell (NSC) differentiation. We show that CMA is active in NSCs, while expression of LAMP2A, the principal limiting component of CMA, is associated with the induction of neurogenesis. Most importantly, overexpression and loss-of-function experiments of LAMP2A in NSCs suggest an inductive role of CMA in neuronal differentiation. Moreover, we demonstrate that LAMP2A is involved in NSC fate decisions by interfering with NOTCH1 signaling pathway. Our data support a model in which LAMP2A-dependent CMA contributes to neuronal fate acquisition through suppression of NOTCH1 signaling, and provide a mechanistic framework that may help explain the reported genetic involvement of LAMP2 gene and CMA in neurodevelopmental disorders.

Characterization of the frameshift c.515dupC knock-in mouse model of HSPB8-associated myopathy (MFM13) and evaluation of Trehalose as autophagy-modulating therapy

These findings support the value of preclinical models for translational studies, and autophagy enhancement as a potential therapeutic strategy for HSPB8-related myopathy, and evaluated trehalose, a natural disaccharide that induces HSPB8 and enhances autophagy.

USP28 Deficiency is Linked to Impaired Ubiquitin-dependent Proteostasis in Huntington’s Disease

Huntingtin is a cell-autonomous regulator of neuropeptide trafficking and clock output

Through targeted genetic knock-down, huntingtin is identified as a cell-autonomous regulator of neuropeptide trafficking, neuronal excitability and circadian output and carries direct relevance for HD therapeutic strategies, particularly those involving huntingtin-lowering approaches.

YTHDC1 functions as a molecular chaperone to suppress ALS-linked hnRNPA1 mutants from aggregation

Proteostasis failure drives multiple neurodegenerative disorders (NDs), and ATP-independent chaperone pathways that support neuronal proteostasis remain poorly defined. Here, we identify the N6-methyladenosine (m6A)-binding protein YTHDC1 as an ATP-independent molecular chaperone, whose activity is mediated by a highly acidic polyaspartate/glutamate (polyD/E) segment. YTHDC1 prevents protein misfolding and aggregation, unfolds kinetically trapped substrates, and resolubilizes pre-formed aggregates. Deletion of the polyD/E segment abolishes these activities, whereas aromatic-cage mutants retain chaperone activity, demonstrating independence from m6A recognition. We identify the amyotrophic lateral sclerosis (ALS)-associated RNA-binding protein hnRNPA1 as a YTHDC1 client. YTHDC1 maintains liquid-like hnRNPA1 condensates, delays fibrillization of disease-associated mutants, and limits stress-granule sequestration, while mitigating mutant hnRNPA1-induced neurite growth defects in primary neurons. These findings define a proteostatic function of YTHDC1 and highlight its chaperone activity as a potential target for mitigating protein aggregation in ALS-related NDs. Researchers identify the RNA-binding protein YTHDC1 as an ATP-independent molecular chaperone that prevents harmful protein aggregation, revealing a link between RNA regulation and protein quality control in neurodegeneration.