The isolated HEPN domain of SACSIN exhibits RNA-binding activity.
7 affiliations
- 1Institute of Biophysics (IBF), National Research Council (CNR), Palermo, Italy.
- 2Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), Palermo, Italy.
- 3Institute of Biophysics (IBF), National Research Council (CNR), Palermo, Italy. [email protected].
- 4Italian Institute of Technology - IIT, Genoa, Italy.
- 5Department of Research, IRCCS-ISMETT (Istituto Mediterraneo Per I Trapianti E Terapie Ad Alta Specializzazione), Palermo, Italy.
- 6Institute of Biophysics (IBF), National Research Council (CNR), Palermo, Italy. [email protected].
- 7Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), Palermo, Italy. [email protected].
Abstract
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder caused by mutations in the SACS gene, though the molecular function of its protein product, SACSIN, remains elusive. Therapeutic strategies for ARSACS are limited, mostly due to the exceptionally large size of SACSIN (~ 520 kDa), which precludes conventional gene therapy and standard molecular delivery methods. Over 200 pathogenic variants, including missense, nonsense and frameshift mutations, have been identified. Regardless of variant type, patients uniformly exhibit cerebellar ataxia, spasticity and peripheral neuropathy. Among them, patients with homozygous frameshift or missense mutations within the SACSIN higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain, suggesting that the alteration of the functional role of the SACSIN HEPN domain could be linked to the manifestation of ARSACS symptoms. Here, we show that the SACSIN HEPN domain can bind RNA in overexpression, corroborating the hypothesis that SACSIN functions as an RNA-binding protein. The interaction of the SACSIN HEPN domain with the RNA regulates the cellular compartmentalization of this domain as well as its propensity to form protein condensates. Conversely, an ARSACS mutated version of the SACSIN HEPN domain (F4574C) showed an impaired RNA-binding activity, a nuclear mis-localization and the predisposition to form protein condensates. Overall, our study unveils an unknown molecular function of the SACSIN HEPN domain that, if formally confirmed also for the full-length SACSIN, can pave the way for innovative therapeutic approaches for ARSACS patients.
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BibTeX
@article{longo2026isolated,
title = {{The isolated HEPN domain of SACSIN exhibits RNA-binding activity.}},
author = {Lisa Longo and Irene Mariani and Antonella Cusimano and Rita Carrotta and Elsa Zacco and Roberta Vazzana and Giuseppe Cappelli and Maria R Mangione and Maria A Costa and Nicola Cuscino and Rosa Passantino and Silvia Vilasi and Alessia Gallo and Vincenzo Martorana and Roberto Giambruno},
journal = {Cellular and molecular life sciences : CMLS},
year = {2026},
month = aug,
doi = {10.1007/s00018-026-06369-w},
url = {https://europepmc.org/article/MED/42873286},
note = {CC BY},
}
RIS
TY - JOUR
TI - The isolated HEPN domain of SACSIN exhibits RNA-binding activity.
AU - Lisa Longo
AU - Irene Mariani
AU - Antonella Cusimano
AU - Rita Carrotta
AU - Elsa Zacco
AU - Roberta Vazzana
AU - Giuseppe Cappelli
AU - Maria R Mangione
AU - Maria A Costa
AU - Nicola Cuscino
AU - Rosa Passantino
AU - Silvia Vilasi
AU - Alessia Gallo
AU - Vincenzo Martorana
AU - Roberto Giambruno
PY - 2026
DA - 2026/08/27
JO - Cellular and molecular life sciences : CMLS
DO - 10.1007/s00018-026-06369-w
UR - https://europepmc.org/article/MED/42873286
AB - Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder caused by mutations in the SACS gene, though the molecular function of its protein product, SACSIN, remains elusive. Therapeutic strategies for ARSACS are limited, mostly due to the exceptionally large size of SACSIN (~ 520 kDa), which precludes conventional gene therapy and standard molecular delivery methods. Over 200 pathogenic variants, including missense, nonsense and frameshift mutations, have been identified. Regardless of variant type, patients uniformly exhibit cerebellar ataxia, spasticity and peripheral neuropathy. Among them, patients with homozygous frameshift or missense mutations within the SACSIN higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain, suggesting that the alteration of the functional role of the SACSIN HEPN domain could be linked to the manifestation of ARSACS symptoms. Here, we show that the SACSIN HEPN domain can bind RNA in overexpression, corroborating the hypothesis that SACSIN functions as an RNA-binding protein. The interaction of the SACSIN HEPN domain with the RNA regulates the cellular compartmentalization of this domain as well as its propensity to form protein condensates. Conversely, an ARSACS mutated version of the SACSIN HEPN domain (F4574C) showed an impaired RNA-binding activity, a nuclear mis-localization and the predisposition to form protein condensates. Overall, our study unveils an unknown molecular function of the SACSIN HEPN domain that, if formally confirmed also for the full-length SACSIN, can pave the way for innovative therapeutic approaches for ARSACS patients.
SN - 1420-682X
SN - 1420-9071
ER -