Ataxin-1 regulates proliferation of hippocampal neural precursors. (13th May 2016)

• Record Type: Journal Article
• Authors: Asher, M.; Johnson, A.; Zecevic, B.; Pease, D.; Cvetanovic, M.
• Is Part Of: Neuroscience. Volume 322(2016)
• Page Start: 54
• Page End: 65
• Publication Date: 2016-05-13
• Subjects: AD Alzheimer's disease -- BrdU 5-bromo-2′-deoxyuridine -- Ct threshold cycle -- DG dentate gyrus -- FGF fibroblast growth factor -- HRP horseradish peroxidase -- NPCs neural precursor cells -- polyQ polyglutamine -- SCA1 spinocerebellar ataxia type 1; ATAXIN-1 -- adult hippocampal neurogenesis -- neural precursor cells -- SCA1; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2016.02.011
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Atxn1 −/− mice have reduced adult hippocampal neurogenesis. Atxn1 −/− hippocampal neural precursor cells (NPCs) proliferate less in vitro . Transfection of mutant ATXN1[82Q] into wild-type NPCs inhibits their proliferation. Abstract: Polyglutamine expansion in the protein ATAXIN-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), an inherited neurodegenerative disease characterized by motor deficits, cognitive impairment and depression. Although ubiquitously expressed, mutant ATXN1 causes neurodegeneration primarily in the cerebellum, which is responsible for the observed motor deficits. The role of ATXN1 outside of the cerebellum and the causes of cognitive deficits and depression in SCA1 are less understood. In this study, we demonstrate a novel role of ATXN1 in the hippocampus as a regulator of adult neurogenesis. Adult hippocampal neurogenesis is the process of generating new hippocampal neurons and is linked to cognition and mood. We found that loss of ATXN1 causes a decrease in hippocampal neurogenesis in ATXN1 null ( Atxn1 −/− ) mice. This decrease was caused by reduced proliferation of neural precursors in the hippocampus of Atxn1 −/− mice, and persisted even when Atxn1 −/− hippocampal neural precursors were removed from their natural environment and grown in vitro, suggesting that ATXN1 affects proliferation in a cell-autonomous manner. Moreover, expression of ATXN1 with a pathological polyglutamine (polyQ) expansion in wild-type neural precursor cells inhibited their proliferation. Our data establish a novel role for ATXN1 in the hippocampus as an intrinsic regulator of precursor cell proliferation, and suggest a mechanism by which polyQ expansion and loss of ATXN1 affect hippocampal function, potentially contributing to cognitive deficits and depression. These results indicate that while depletion of ATXN1 is a promising therapeutic approach to treat the cerebellar aspects of SCA1, this approach should be employed with caution given the potential for side effects on hippocampal function with loss of wild-type ATXN1.