Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1.
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (Q) repeat tract in the protein ataxin-1 (ATXN1). Beginning as a cerebellar ataxic disorder, SCA1 progresses to involve the cerebral cortex, hippocampus, and brainstem. Using SCA1 knock-in mice that mirror the complexity of the human disease, we report a significant decrease in the capacity of adult neuronal progenitor cells (NPCs) to proliferate. Remarkably, a decrease in NPCs proliferation can be observed in vitro, outside the degenerative milieu of surrounding neurons or glia, demonstrating that mutant ATXN1 acting cell autonomously within progenitor cells interferes with their ability to proliferate. Our findings suggest that compromised adult neurogenesis contributes to the progressive pathology of the disease particularly in areas such as the hippocampus and cerebral cortex where stem cells provide neurotropic factors and participate in adult neurogenesis. These findings not only shed light on the biology of the disease but also have therapeutic implications in any future stem cell-based clinical trials.
Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
Marija
M
Cvetanovic
Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Yuan-Shih
YS
Hu
Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. p-opal@northwestern.edu.|Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. p-opal@northwestern.edu.
Puneet
P
Opal
D053687:Adult Stem Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000067696:Ataxin-1 / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D007150:Immunohistochemistry; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000378:metabolism*; D055153:Stem Cell Niche / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000067696:Ataxin-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D001973:Bromodeoxyuridine
Neurogenesis; Proliferation; SCA1; Spinocerebellar ataxia type 1