TY - JOUR
T1 - Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1
AU - Edamakanti, Chandrakanth Reddy
AU - Do, Jeehaeh
AU - Didonna, Alessandro
AU - Martina, Marco
AU - Opal, Puneet
N1 - Funding Information:
We thank members of the Opal lab for their suggestions, Vicky Brandt for thoughtful comments on the manuscript, James Scott Coy-Dibley for help with mouse genotyping, and Arnulf H. Koep-pen, who provided SCA-1 brain material. Autopsies were performed through a national tissue donation program supported by the National Ataxia Foundation. PO is supported by NIH grants 1R01 NS062051 and 1R01 NS082351. MM is supported by NIH grant 1R21NS090346.
Funding Information:
Quantitative analysis of basket score in human brain samples. Arnulf H. Koeppen (Albany Medical College, Albany, New York, USA) provided brain samples derived from autopsies of 12 genetically confirmed cases of SCA1 (Supplemental Table 1). All SCA1 brain samples were fixed in ice-cold 4% neutral formaldehyde solution as soon as harvested and embedded in paraffin. Autopsies were performed through a national tissue donation program supported by the National Ataxia Foundation.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1, which is involved in transcriptional regulation. Although symptoms appear relatively late in life, primarily from cerebellar dysfunction, pathogenesis begins early, with transcriptional changes detectable as early as a week after birth in SCA1-knockin mice. Given the importance of this postnatal period for cerebellar development, we asked whether this region might be developmentally altered by mutant ATXN1. We found that expanded ATXN1 stimulates the proliferation of postnatal cerebellar stem cells in SCA1 mice. These hyperproliferating stem cells tended to differentiate into GABAergic inhibitory interneurons rather than astrocytes; this significantly increased the GABAergic inhibitory interneuron synaptic connections, disrupting cerebellar Purkinje cell function in a non-cell autonomous manner. We confirmed the increased basket cell-Purkinje cell connectivity in human SCA1 patients. Mutant ATXN1 thus alters the neural circuitry of the developing cerebellum, setting the stage for the later vulnerability of Purkinje cells to SCA1. We propose that other late-onset degenerative diseases may also be rooted in subtle developmental derailments.
AB - Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1, which is involved in transcriptional regulation. Although symptoms appear relatively late in life, primarily from cerebellar dysfunction, pathogenesis begins early, with transcriptional changes detectable as early as a week after birth in SCA1-knockin mice. Given the importance of this postnatal period for cerebellar development, we asked whether this region might be developmentally altered by mutant ATXN1. We found that expanded ATXN1 stimulates the proliferation of postnatal cerebellar stem cells in SCA1 mice. These hyperproliferating stem cells tended to differentiate into GABAergic inhibitory interneurons rather than astrocytes; this significantly increased the GABAergic inhibitory interneuron synaptic connections, disrupting cerebellar Purkinje cell function in a non-cell autonomous manner. We confirmed the increased basket cell-Purkinje cell connectivity in human SCA1 patients. Mutant ATXN1 thus alters the neural circuitry of the developing cerebellum, setting the stage for the later vulnerability of Purkinje cells to SCA1. We propose that other late-onset degenerative diseases may also be rooted in subtle developmental derailments.
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U2 - 10.1172/JCI96765
DO - 10.1172/JCI96765
M3 - Article
C2 - 29533923
AN - SCOPUS:85048298120
VL - 128
SP - 2252
EP - 2265
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -