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Pathogenic CLP1 p.R140H mutation alters mRNA processing in human motor neurons (total RNA-seq)

ABSTRACT: Pontocerebellar Hypoplasia Type 10 (PCH10) is a childhood neurodegenerative disease caused by bi-allelic p.R140H variants in CLP1, a multifunctional RNA kinase, by unknown pathophysiological mechanisms. Here, we combine novel patient data with mutation-specific in vivo and in vitro models to define motor neuron dysfunction as a penetrant, prominent feature of PCH10 and uncover a previously unrecognized mRNA misprocessing signature in motor neurons that likely contributes to pathology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183870 | GEO | 2021/11/01

REPOSITORIES: GEO

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Pathogenic CLP1 p.R140H mutation alters mRNA processing in human motor neurons (tRNA-seq)

Project description:Pontocerebellar Hypoplasia Type 10 (PCH10) is a childhood neurodegenerative disease caused by bi-allelic p.R140H variants in CLP1, a multifunctional RNA kinase, by unknown pathophysiological mechanisms. Here, we combine novel patient data with mutation-specific in vivo and in vitro models to define motor neuron dysfunction as a penetrant, prominent feature of PCH10 and uncover a previously unrecognized mRNA misprocessing signature in motor neurons that likely contributes to pathology.

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The Clp1 R140H mutation alters tRNA metabolism and mRNA 3’ processing in mouse models of pontocerebellar hypoplasia

Project description:Homozygous mutation of the RNA kinase CLP1 causes pontocerebellar hypoplasia type 10 (PCH10), a pediatric neurodegenerative disease. CLP1 is associated with the tRNA splicing endonuclease complex and the cleavage and polyadenylation machinery, but its function remains unclear. We generated two mouse models of PCH10: one homozygous for the disease-associated Clp1 mutation, R140H, and one heterozygous for this mutation and a null allele. Both models exhibit loss of lower motor neurons and neurons of the deep cerebellar nuclei. To explore whether Clp1 mutation impacts tRNA splicing, we profiled the products of intron-containing tRNA genes. While mature tRNAs were expressed at normal levels in mutant mice, numerous other products of intron-containing tRNA genes were dysregulated, with pre-tRNAs, introns, and certain tRNA fragments upregulated, and other fragments downregulated. However, the spatiotemporal patterns of dysregulation did not support a role in pathogenicity for most altered tRNA products. To elucidate the effect of Clp1 mutation on pre-mRNA cleavage, we analyzed poly(A) site (PAS) usage and gene expression in Clp1R140H/- spinal cord. PAS usage was shifted from proximal to distal sites in the mutant mouse, particularly in short and closely spaced genes. Many such genes also were expressed at lower levels in the Clp1R140H/- mouse, possibly as a result of impaired transcript maturation. These findings are consistent with the hypothesis that select genes are particularly dependent upon CLP1 for proper pre-mRNA cleavage, suggesting that the contribution of mRNA 3’ processing to pathogenesis in PCH10 merits further investigation.

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CLP1 links tRNA metabolism to progressive motor-neuron loss

Project description:CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clp1 (Clp1K/K) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1K/K mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53. RNA was extracted from spinal cord of 3 Clp1 knock-out mice and 3 wild type mice (15 days old, male, all samples age and sex matched) and submitted to differential splicing analysis using Affymetrix Exon microarrays. Differential splicing analysis was performed between the Clp1 KO and WT samles employing a custom CDF, that was based on a complete re-alignment of oligonucleotide probes to the genome and transcriptome (Ensembl 52, ASTD 1.1; further information on http://bioinfo.i-med.ac.at).

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CLP1 links tRNA metabolism to progressive motor-neuron loss

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Pathogenic CLP1 p.R140H mutation alters mRNA processing in human motor neurons

Project description:Pathogenic CLP1 p.R140H mutation alters mRNA processing in human motor neurons

| PRJNA762246 | ENA

The Clp1 R140H mutation alters tRNA metabolism and mRNA 3’ processing in mouse models of pontocerebellar hypoplasia

Project description:The Clp1 R140H mutation alters tRNA metabolism and mRNA 3’ processing in mouse models of pontocerebellar hypoplasia

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Pathogenic CLP1 p.R140H mutation alters mRNA processing in human motor neurons (tRNA-seq)

Project description:Pathogenic CLP1 p.R140H mutation alters mRNA processing in human motor neurons (tRNA-seq)

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Pathogenic CLP1 p.R140H mutation alters mRNA processing in human motor neurons (PAC-seq)

Project description:Pathogenic CLP1 p.R140H mutation alters mRNA processing in human motor neurons (PAC-seq)

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