BDNF is altered in a brain-region specific manner and rescues deficits in Spinocerebellar Ataxia Type 1.

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, dominantly inherited neurodegenerative disease caused by the expanded polyQ tract in the protein ATAXIN1 (ATXN1) and characterized by progressive motor and cognitive impairments. There are no disease-modifying treatments or cures for SCA1. Brain-derived neurotrophic factor (BDNF) plays important role in cerebellar physiology and has shown therapeutic potential for cerebellar pathology in the transgenic mouse model of SCA1, ATXN1[82Q] line that overexpress mutant ATXN1 under a cerebellar Purkinje-cell-specific promoter. Here we demonstrate decreased expression of brain derived neurotrophic factor (BDNF) in the cerebellum and medulla of patients with SCA1. Early stages of disease seem most amenable to therapy. Thus, we next quantified Bdnf expression in Atxn1154Q/2Q mice, a knock-in mouse model of SCA1, during the early symptomatic disease stage in four clinically relevant brain regions: cerebellum, medulla, hippocampus and motor cortex. We found that during the early stages of disease, Bdnf mRNA expression is reduced in the hippocampus and cerebellum, while it is increased in the cortex and brainstem. Importantly, we observed that pharmacological delivery of recombinant BDNF improved motor and cognitive performance, and mitigated pathology in the cerebellum and hippocampus of Atxn1154Q/2Q mice. Our findings demonstrate brain-region specific deficiency of BDNF in SCA1 and show that reversal of low BDNF levels offers the potential for meaningful treatment of motor and cognitive deficits in SCA1.

• Authors: Juao-Guilherme Rosa, Katherine Hamel, Alyssa Soles, Carrie Sheeler, Ella Borgenheimer, Stephen Gilliat, Kaelin Sbrocco, Ferris Ghanoum, Hillary P Handler, Colleen Forster, Orion Rainwater, Marija Cvetanovic
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 178 Pg. 106023 (03 2023) ISSN: 1095-953X [Electronic] United States
• PMID: 36724861 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Brain-Derived Neurotrophic Factor
• Ataxin-1

Topics

• Mice
• Animals
• Brain-Derived Neurotrophic Factor (genetics, metabolism)
• Ataxin-1 (genetics, metabolism)
• Spinocerebellar Ataxias (metabolism)
• Cerebellum (pathology)
• Mice, Transgenic
• Purkinje Cells (metabolism)
• Disease Models, Animal