期刊
MOVEMENT DISORDERS
卷 36, 期 12, 页码 2780-2794出版社
WILEY
DOI: 10.1002/mds.28750
关键词
striatum; X-linked dystonia parkinsonism; TAF1; cholinergic interneurons
资金
- Department of Health and Human Services National Institutes of Health National Institute of Neurological Disorders and Stroke [R01-NS-100529]
- Collaborative Center for X-linked Dystonia Parkinsonism at MGH
- Taube HD Stem Cell Consortium
- Dystonia Medical Research Foundation
This study investigates the behavioral and transcriptomic effects of decreased cTAF1 and/or nTAF1 in vivo. Knockdown of Taf1 in newborn animals results in motor deficits and transcriptomic alterations in multiple neuronal pathways, including the cholinergic synapse. The study provides new insights into the requirement for TAF1 in maintaining striatal cholinergic neurons postnatally and its implications in inherited forms of dystonia.
Background X-linked dystonia parkinsonism is a generalized, progressive dystonia followed by parkinsonism with onset in adulthood and accompanied by striatal neurodegeneration. Causative mutations are located in a noncoding region of the TATA-box binding protein-associated factor 1 (TAF1) gene and result in aberrant splicing. There are 2 major TAF1 isoforms that may be decreased in symptomatic patients, including the ubiquitously expressed canonical cTAF1 and the neuronal-specific nTAF1. Objective The objective of this study was to determine the behavioral and transcriptomic effects of decreased cTAF1 and/or nTAF1 in vivo. Methods We generated adeno-associated viral (AAV) vectors encoding microRNAs targeting Taf1 in a splice-isoform selective manner. We performed intracerebroventricular viral injections in newborn mice and rats and intrastriatal infusions in 3-week-old rats. The effects of Taf1 knockdown were assayed at 4 months of age with evaluation of motor function, histology, and RNA sequencing of the striatum, followed by its validation. Results We report motor deficits in all cohorts, more pronounced in animals injected at P0, in which we also identified transcriptomic alterations in multiple neuronal pathways, including the cholinergic synapse. In both species, we show a reduced number of striatal cholinergic interneurons and their marker mRNAs after Taf1 knockdown in the newborn. Conclusion This study provides novel information regarding the requirement for TAF1 in the postnatal maintenance of striatal cholinergic neurons, the dysfunction of which is involved in other inherited forms of dystonia. (c) 2021 International Parkinson and Movement Disorder Society
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