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Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay

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Abstract

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion (Bβ2 KO) nor fission (Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.

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No datasets were generated or analysed during the current study.

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Acknowledgements

We acknowledge technical assistance by Yufang Kong, Kathleen Kelley, Gail Healy, and Marisol Lauffer. Many of the experiments were conducted at the Neural Circuits and Behavior Core of the Iowa Neuroscience Institute. Sacs KO mice were a kind gift of Bernard Brais, McGill (3), Akap1 KO mice were donated by G. Stanley McKnight, U. Washington (29), and Bβ2 KO mice were generated at the U. Iowa Mouse KO Core Facility. The data used for Fig. 1 in this manuscript were obtained from the Genotype-Tissue Expression (GTEx) Portal on 3/8/24. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

Funding

This work was supported by the Ataxia of Charlevoix-Saguenay Foundation. Additional support was provided by R21 AG080472-01 and the Simons Foundation Autism Research Initiative (SFARI).

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Authors and Affiliations

  1. Department of Neuroscience and Pharmacology, University of Iowa, Carver College of Medicine, Bowen Science Building, 51 Newton Road, Iowa City, IA, 52242, USA

    Chunling Chen, Chian Ju Jong & Stefan Strack

  2. Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine, Bowen Science Building, 51 Newton Road, Iowa City, IA, 52242, USA

    Ronald A. Merrill

  3. Iowa Neuroscience Institute, Intellectual and Developmental Disabilities Research Center, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA

    Stefan Strack

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  1. Chunling Chen
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Contributions

RAM and SS conceptualized the study. CC, RAM, and CJJ performed experiments, and CC and SS prepared the figures and wrote the manuscript. All authors read, edited, and approved the final manuscript before submission.

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Correspondence to Stefan Strack.

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Chen, C., Merrill, R.A., Jong, C.J. et al. Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay. Cerebellum (2024). https://doi.org/10.1007/s12311-024-01701-1

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