Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay

Chunling Chen; Ronald A Merrill; Chian Ju Jong; Stefan Strack

doi:10.21203/rs.3.rs-4178088/v1

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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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Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay

Chunling Chen, Ronald A Merrill, Chian Ju Jong and Stefan Strack

Research square

04/10/2024

DOI: 10.21203/rs.3.rs-4178088/v1

PMCID: PMC11042405

PMID: 38659734

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https://doi.org/10.21203/rs.3.rs-4178088/v1View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with knock-out (KO) mice and patient-derived fibroblasts suggested that 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 ( β KO) nor fission ( KO) influenced progression of motor symptoms in KO mice. However, our studies identified profound learning and memory deficits in aged 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.

Details

Title: Subtitle: Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay
Creators: Chunling Chen - University of Iowa
Ronald A Merrill - University of Iowa
Chian Ju Jong - University of Iowa
Stefan Strack - University of Iowa
Resource Type: Preprint
Publication Details: Research square
DOI: 10.21203/rs.3.rs-4178088/v1
PMID: 38659734
PMCID: PMC11042405
Language: English
Date posted: 04/10/2024
Academic Unit: Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
Record Identifier: 9984618417602771

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