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Gain of toxic function by long-term SMN overexpression in the sensory-motor circuit.

ABSTRACT: The neurodegenerative disease spinal muscular atrophy (SMA) is a leading genetic cause of infant death caused by deficiency in the survival motor neuron (SMN) protein. Currently approved SMA treatments aim to restore SMN, but the potential for expression of SMN beyond physiological levels is a unique feature of AAV9-SMN gene therapy. Here, we show that long-term AAV9-mediated SMN overexpression in mouse models induces dose-dependent, late-onset motor dysfunction associated with loss of proprioceptive synapses and neurodegeneration. Mechanistically, aggregation of overexpressed SMN in the cytoplasm of motor circuit neurons sequesters components of small nuclear ribonucleoproteins (snRNPs), leading to splicing dysregulation and widespread transcriptome abnormalities with prominent signatures of neuroinflammation and innate immune response. Thus, long-term SMN overexpression can interfere with its normal activity in RNA regulation and trigger SMA-like pathogenic events through toxic gain of function mechanisms. These unanticipated, SMN-dependent and neuron-specific liabilities of AAV9-SMN warrant further evaluation of the long-term safety of gene therapy in SMA.

ORGANISM(S): Mus musculus

PROVIDER: GSE149391 | GEO | 2021/02/01

REPOSITORIES: GEO

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Trancriptional regulation by axonal SMN on motor neuron cells

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2012-01-07 | E-MEXP-3402 | biostudies-arrayexpress

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2022-06-30 | GSE190426 | GEO

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2020-08-11 | GSE154106 | GEO

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2020-04-30 | GSE145146 | GEO

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Quantitative proteomic analysis of Survival Motor Neuron (SMN) missense mutants in Drosophila

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2024-04-11 | PXD046801 | Pride

SMN deficiency in spinal muscular atrophy causes widespread intron retention and DNA damage

Project description:Spinal muscular atrophy is the leading genetic cause of infant mortality and is caused by homozygous loss of the SMN1 gene. We investigated global transcriptome changes in the spinal cord of inducible SMA mice. SMN depletion caused widespread retention of introns with weak splice sites or belonging to the minor (U12) class. We further demonstrated accumulation of DNA double strand breaks in the spinal cord of SMA mice and in human SMA cell culture models. DNA damage was partially rescued by suppressing the formation of R-loops, which accumulated over retained introns. We propose that instead of single gene effects, pervasive splicing defects caused by SMN deficiency trigger a global DNA damage and stress response, thus compromising motor neuron survival.

2017-03-21 | GSE87281 | GEO

SMN and Symmetric Arginine Dimethylation of RNAP II CTD Control Termination

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2015-12-31 | E-GEOD-73379 | biostudies-arrayexpress

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