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17q21.31 locus regulates Parkinson’s disease relevant pathways through KANSL1 activity

ABSTRACT: 17q21.31 locus regulates Parkinson’s disease relevant pathways through KANSL1 activity

PROVIDER: PRJNA1195127 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31634914_1.fastq.gz	Fastqsanger.gz
	SRR31634914_2.fastq.gz	Fastqsanger.gz
	SRR31634915_1.fastq.gz	Fastqsanger.gz
	SRR31634915_2.fastq.gz	Fastqsanger.gz
	SRR31634916_1.fastq.gz	Fastqsanger.gz

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17q21.31 locus regulates Parkinson’s disease relevant pathways through KANSL1 activity

Project description:An inversion polymorphism at the 17q21.31 locus defines the H1 and H2 haplotypes, with the former linked to multiple neurodegenerative disorders, including an increased risk of Parkinson’s disease (PD). Although the high linkage disequilibrium at this locus has made it difficult to decipher which gene(s) drive the PD association, there is increasing evidence to support the role of KANSL1 as a risk gene. KANSL1 has been shown to regulate the expression of some PD-associated genes and pathways, likely as part of the histone acetylating non-specific lethal (NSL) complex. Here for the first time, we studied the global effects of 17q21.31 haplotype variation using bulk and single-nuclear RNA-sequencing data from control and PD patient brain. We first analysed differential gene expression across haplotype groups, and then assessed the contribution of KANSL1 by comparing with the results of an siRNA knockdown in neuronal and glial human cell lines. We demonstrated that the PD risk-associated H1 haplotype downregulates autophagy, lysosomal and mitochondrial processes, all of which have already been implicated in PD aetiology. Furthermore, these effects were apparent in both neuronal and glial cell types, and in the case of the latter, appear to be associated with the modulation of innate and adaptive immune responses. Thus, we identify important links between NSL complex activity and PD pathophysiology that can be leveraged for novel therapeutic interventions.

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Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition.

Project description:Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.

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