Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS

Cellular and Molecular Life Sciences : CMLS
Anika M HelferichJochen H Weishaupt

Abstract

Genetic and functional studies suggest diverse pathways being affected in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), while knowledge about converging disease mechanisms is rare. We detected a downregulation of microRNA-1825 in CNS and extra-CNS system organs of both sporadic (sALS) and familial ALS (fALS) patients. Combined transcriptomic and proteomic analysis revealed that reduced levels of microRNA-1825 caused a translational upregulation of tubulin-folding cofactor b (TBCB). Moreover, we found that excess TBCB led to depolymerization and degradation of tubulin alpha-4A (TUBA4A), which is encoded by a known ALS gene. Importantly, the increase in TBCB and reduction of TUBA4A protein was confirmed in brain cortex tissue of fALS and sALS patients, and led to motor axon defects in an in vivo model. Our discovery of a microRNA-1825/TBCB/TUBA4A pathway reveals a putative pathogenic cascade in both fALS and sALS extending the relevance of TUBA4A to a large proportion of ALS cases.

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Citations

Aug 1, 2020·Frontiers in Neuroscience·Ramya RanganathanJanine Kirby
May 30, 2019·Frontiers in Neurology·Udaya Geetha VijayakumarStephanie Marie-Rose Duguez
Oct 3, 2020·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Lin Wang, Lijuan Zhang
Feb 7, 2019·Frontiers in Genetics·Zoe Butti, Shunmoogum A Patten
Nov 27, 2020·Journal of Neurology, Neurosurgery, and Psychiatry·Virgilio KmetzschUNKNOWN PREV-DEMALS study group
Dec 8, 2020·Frontiers in Cellular Neuroscience·María José Castellanos-MontielThomas M Durcan
May 7, 2021·Computational and Mathematical Methods in Medicine·Dingsheng LiuXuefeng Gu
May 11, 2021·Frontiers in Cell and Developmental Biology·Sofia NolascoJuan Carlos Zabala
Jul 10, 2021·Acta neurologica Belgica·Evrim Aksu-MengesErsin Tan

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Datasets Mentioned

BETA
50428924

Methods Mentioned

BETA
PCR
PCRs
transfections
transfection
chips
pulldown
Assay
immunoprecipitation
confocal microscopy
transgenic

Software Mentioned

Affymetrix Expression Console Software
Zeiss
AxioVision
ImageJ
miRWalk2
GraphPadPrism
LabVIEW
Genesis
LAS X microscope

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