SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington’s disease models

Huntington’s disease (HD) is a neurodegenerative disorder caused by mutations in the huntingtin gene resulting in an extended polyglutamine (polyQ) stretch in the protein, which is prone to aggregation and toxicity. In addition to a proteostasis imbalance, growing evidence highlights the role of mitochondrial dysfunction in HD progression. Here we explore the role of SIR-2.3/SIRT4, a mitochondrial sirtuin, in polyQ-expanded peptides and mutant huntingtin (mHTT) toxicity using C. elegans and mammalian models. Notably, loss of sir-2.3 function results in neuronal protection mediated by AMPK activation and enhanced autophagy. These neuroprotective effects require the transcription factors DAF-16/FOXO and NHR-49, which regulate autophagy and metabolism. To explore the translational potential of these findings, we used soft ATP synthase inhibitors to mimic sir-2.3 ablation, successfully reducing mHTT-induced neuronal toxicity. These results identify the SIRT4-AMPK axis as a critical regulator linking mitochondrial metabolism, autophagy, and neuronal homeostasis in HD. These findings not only advance our understanding of HD pathogenesis but also offer promising therapeutic targets for restoring proteostasis and neuronal resilience capacity against neurodegenerative diseases.

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Publication Details

Journal
Cell Communication and Signaling
Published
2026-01-15
DOI
https://doi.org/10.1186/s12964-026-02655-z
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
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article

SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington’s disease models

Julia Tortajada-Pérez, Andrea del Valle Carranza, Rafael P. Vázquez‐Manrique, Christian Néri et al.
Cell Communication and Signaling
Genetic Neurodegenerative Diseases
article

SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington’s disease models

Julia Tortajada-Pérez, Andrea del Valle Carranza, Rafael P. Vázquez‐Manrique, Christian Néri, Seda Koyuncu, David Vı́lchez, Cristina Trujillo-Del Río, Ana Pilar Gómez-Escribano, Mar Collado-Pérez, José M. Millán, Marta Isabel Roca, Yolanda Sanz, Carlos Mora, Agustín Lahoz
article en

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by mutations in the huntingtin gene resulting in an extended polyglutamine (polyQ) stretch in the protein, which is prone to aggregation and toxicity. In addition to a proteostasis imbalance, growing evidence highlights the role of mitochondrial dysfunction in HD progression. Here we explore the role of SIR-2.3/SIRT4, a mitochondrial sirtuin, in polyQ-expanded peptides and mutant huntingtin (mHTT) toxicity using C. elegans and mammalian models. Notably, loss of sir-2.3 function results in neuronal protection mediated by AMPK activation and enhanced autophagy. These neuroprotective effects require the transcription factors DAF-16/FOXO and NHR-49, which regulate autophagy and metabolism. To explore the translational potential of these findings, we used soft ATP synthase inhibitors to mimic sir-2.3 ablation, successfully reducing mHTT-induced neuronal toxicity. These results identify the SIRT4-AMPK axis as a critical regulator linking mitochondrial metabolism, autophagy, and neuronal homeostasis in HD. These findings not only advance our understanding of HD pathogenesis but also offer promising therapeutic targets for restoring proteostasis and neuronal resilience capacity against neurodegenerative diseases.

Cell Communication and SignalingVol. 24(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Universitat de València (ES), University of Cologne (DE), Sorbonne Université (FR), Instituto de Agroquímica y Tecnología de Alimentos (ES), Institut de Biologie Paris-Seine (FR), Centre for Biomedical Network Research on Rare Diseases (ES), Centro de Investigación Biomédica en Red (ES), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), University Hospital Cologne (DE), INCLIVA Health Research Institute (ES), Instituto de Investigación de Enfermedades Raras (ES), Instituto de Investigación Sanitaria La Fe (ES), Adaptation Biologique et Vieillissement (FR), Universitat Politècnica de València (ES)
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Genetic Neurodegenerative Diseases
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