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Evidence for toxic CAG trinucleotide repeats contributing to Huntington’s disease though RNA interference

ABSTRACT: Evidence for toxic CAG trinucleotide repeats contributing to Huntington’s disease though RNA interference

PROVIDER: PRJNA832695 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18937635.fastq.gz	Fastqsanger.gz
	SRR18937636.fastq.gz	Fastqsanger.gz
	SRR18937637.fastq.gz	Fastqsanger.gz
	SRR18937638.fastq.gz	Fastqsanger.gz
	SRR18937639.fastq.gz	Fastqsanger.gz

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Evidence for toxic CAG trinucleotide repeats contributing to Huntington’s disease though RNA interference

Project description:Evidence for toxic CAG trinucleotide repeats contributing to Huntington’s disease though RNA interference

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Evidence for toxic CAG trinucleotide repeats contributing to Huntington’s disease though RNA interference

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Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s Disease

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Project description:Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington’s disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell cultures, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. Suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.

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