Cerebellar mitochondrial dysfunction coincides with structural and behavioral abnormalities in 3q29Del mice
- 1Fralin Biomedical Research Institute at Virginia Tech Carilion
Abstract
3q29 deletion (3q29Del) is a genetic risk variant for autism spectrum disorder and schizophrenia that often results in developmental delays, cognitive disability, and impaired fine motor function. People with 3q29Del have reduced cerebellar volume, which correlates with symptom severity, and many 3q29Del-associated phenotypes also commonly occur after cerebellar injury or dysfunction. However, it is unknown whether the existing 3q29Del mouse model recapitulates the cerebellar dysfunction observed in humans. To characterize cerebellar phenotypes and uncover pathological differences in the 3q29Del mouse model, we investigated cerebellar structure, motor and vocal behaviors, protein expression, and mitochondrial function. We found uniformly reduced cerebellar volume in 3q29Del mice. Behavioral assays revealed vocal impairments in 3q29Del pups, fine motor impairments in adult mice, and reduced social mating calls in adult male mice. Proteomic analysis revealed enrichment of synaptic and mitochondrial proteins among the differentially expressed proteins in 3q29Del cerebellum tissue. Furthermore, mitochondria from 3q29Del mouse cerebellum displayed reduced oxygen flux and increased electron leak. These results recapitulate many human 3q29Del phenotypes in the 3q29Del mouse model and indicate mitochondrial dysfunction as a potential driver of 3q29Del pathology. Our findings also point to cerebellar involvement in 3q29Del phenotypes and provide a foundation for further research on cerebellar development in 3q29Del.
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BibTeX
@misc{kretzer2026cerebellar,
title = {{Cerebellar mitochondrial dysfunction coincides with structural and behavioral abnormalities in 3q29Del mice}},
author = {M. K. Kretzer and E. Arnulfo Candelario and R. Montalvo and X. Leng and J. A. Coello and Z. Ou and A. E. Pozo-Aranda and J. G. Mulle and Z. Yan and R. H. Purcell and M. E. van der Heijden},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754481},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754481v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cerebellar mitochondrial dysfunction coincides with structural and behavioral abnormalities in 3q29Del mice
AU - M. K. Kretzer
AU - E. Arnulfo Candelario
AU - R. Montalvo
AU - X. Leng
AU - J. A. Coello
AU - Z. Ou
AU - A. E. Pozo-Aranda
AU - J. G. Mulle
AU - Z. Yan
AU - R. H. Purcell
AU - M. E. van der Heijden
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754481
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754481v1
AB - 3q29 deletion (3q29Del) is a genetic risk variant for autism spectrum disorder and schizophrenia that often results in developmental delays, cognitive disability, and impaired fine motor function. People with 3q29Del have reduced cerebellar volume, which correlates with symptom severity, and many 3q29Del-associated phenotypes also commonly occur after cerebellar injury or dysfunction. However, it is unknown whether the existing 3q29Del mouse model recapitulates the cerebellar dysfunction observed in humans. To characterize cerebellar phenotypes and uncover pathological differences in the 3q29Del mouse model, we investigated cerebellar structure, motor and vocal behaviors, protein expression, and mitochondrial function. We found uniformly reduced cerebellar volume in 3q29Del mice. Behavioral assays revealed vocal impairments in 3q29Del pups, fine motor impairments in adult mice, and reduced social mating calls in adult male mice. Proteomic analysis revealed enrichment of synaptic and mitochondrial proteins among the differentially expressed proteins in 3q29Del cerebellum tissue. Furthermore, mitochondria from 3q29Del mouse cerebellum displayed reduced oxygen flux and increased electron leak. These results recapitulate many human 3q29Del phenotypes in the 3q29Del mouse model and indicate mitochondrial dysfunction as a potential driver of 3q29Del pathology. Our findings also point to cerebellar involvement in 3q29Del phenotypes and provide a foundation for further research on cerebellar development in 3q29Del.
ER -