期刊
BRAIN
卷 144, 期 -, 页码 2302-2309出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awab130
关键词
tau; parkinsonism; tauopathies; microPET; RNA therapy
资金
- Argentinean National Scientific and Technical Research Council-CONICET
- National Agency for Science and Technology [PICT 2018-03924]
- CurePSP [665-2019-07]
- International Brain Research Organization
- International Society for Neurochemistry (ISN-CAEN)
Tauopathies are caused by abnormal metabolism of tau protein and an imbalance in 3R and 4R tau can lead to motor coordination impairments. Modulation of tau isoform content may be a potential disease-modifying therapy for primary tauopathies.
Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein tau (MAPT), which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in MAPT pre-mRNA produces equal amounts of protein isoforms with either three (3R) or four (4R) microtubule binding domains. Imbalance in the 3R:4R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal. Here we report motor coordination impairments in the htau mouse model of tauopathy which harbour abnormal 3R:4R tau isoforms content, and in contrast to TauKO mice, are unresponsive to L-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses indicated the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results suggest that abnormal striatal tau isoform content might lead to parkinsonian-like phenotypes and demonstrate a proof of concept that modulation of tau mis-splicing is a plausible disease-modifying therapy for some primary tauopathies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据