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

Autor: Rosa JG; Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America. Electronic address: jrosa@bu.edu., Hamel K; Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America. Electronic address: hamel044@umn.edu., Soles A; Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America. Electronic address: soles010@umn.edu., Sheeler C; Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America. Electronic address: sheel031@umn.edu., Borgenheimer E; Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America. Electronic address: Ella.Borgenheimer@bcm.edu., Gilliat S; Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America. Electronic address: gilli432@umn.edu., Sbrocco K; Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America. Electronic address: sbroc005@umn.edu., Ghanoum F; Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America. Electronic address: ghann008@umn.edu., Handler HP; Institute for Translational Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America; Department of Lab Medicine and Pathology, United States of America. Electronic address: handl032@umn.edu., Forster C; BLS Histology, IHC Laboratory, United States of America. Electronic address: cforster@umn.edu., Rainwater O; Department of Lab Medicine and Pathology, United States of America. Electronic address: rainw001@umn.edu., Cvetanovic M; Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America; Institute for Translational Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America. Electronic address: mcvetano@umn.edu.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2023 Mar; Vol. 178, pp. 106023. Date of Electronic Publication: 2023 Jan 29.
DOI: 10.1016/j.nbd.2023.106023
Abstrakt: 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 Atxn1 154Q/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 Atxn1 154Q/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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: