Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at Chr16q11.2 and on the MAPT H1 allele

Mp, Soutar; Melandri, Daniela; O’Callaghan, Benjamin; Annuario, Emily; Ae, Monaghan; Welsh, Natalie J.; D’Sa, Karishma; Guelfi, Sebastian; Zhang, David; Pittman, Alan; Trabzuni, Daniah; Ks, Pan; Da, Kia; Bictash, Magda; Gandhi, Sonia; Houlden, Henry; Mr, Cookson; Wood, Nicholas W.; Ab, Singleton; Whiting, Paul J.; Blauwendraat, Cornelis; Aj, Whitworth; Manzoni, Claudia; Ryten, Mina; Lewis, Penelope A.; Plun‐Favreau, Hélène

doi:10.1101/2020.01.06.896241

Cited by 8 publications

(8 citation statements)

References 51 publications

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“…We also acknowledge that although the H1 inversion haplotype on chromosome 17 is commonly named after MAPT, it contains a number of other genes, and the mechanism driving the association signal for PD risk has yet to be unequivocally established. Recent evidence suggest that rather than MAPT, the disease-relevant gene could be the neighboring KANSL1, which is involved in autophagy regulation (52).…”

Section: Discussionmentioning

confidence: 99%

APOE and MAPT Are Associated With Dementia in Neuropathologically Confirmed Parkinson's Disease

et al. 2021

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Introduction: Cognitive decline and dementia are common and debilitating non-motor phenotypic features of Parkinson's disease with a variable severity and time of onset. Common genetic variation of the Apolipoprotein E (APOE) and micro-tubule associated protein tau (MAPT) loci have been linked to cognitive decline and dementia in Parkinson's disease, although studies have yielded mixed results. To further elucidate the influence of APOE and MAPT variability on dementia in Parkinson's disease, we genotyped postmortem brain tissue samples of clinically and pathologically well-characterized Parkinson's donors and performed a survival analysis of time to dementia.Methods: We included a total of 152 neuropathologically confirmed Parkinson's disease donors with or without clinical dementia during life. We genotyped known risk variants tagging the APOE ε4 allele and MAPT H1/H2 inversion haplotype. Cox proportional hazards regression analyses adjusted for age at onset, sex and genetic principal components were performed to assess the association between the genetic variants and time from motor onset to onset of dementia.Results: We found that both the APOE ε4 allele (HR 1.82, 95 % CI 1.16–2.83, p = 0.009) and MAPT H1-haplotype (HR 1.71, 95 % CI 1.06–2.78, p = 0.03) were associated with earlier development of dementia in patients with Parkinson's disease.Conclusion: Our results provide further support for the importance of APOE ε4 and MAPT H1-haplotype in the etiology of Parkinson's disease dementia, with potential future relevance for risk stratification and patient selection for clinical trials of therapies targeting cognitive decline in Parkinson's disease.

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Section: Discussionmentioning

confidence: 99%

APOE and MAPT Are Associated With Dementia in Neuropathologically Confirmed Parkinson's Disease

et al. 2021

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“…However, while tau pathology can occur alongside –α synuclein inclusions in the substantia nigra 16, 17 , it is not a typical neuropathological feature of PD 15 . The causal gene underlying the genetic association across the 17q21.31 locus with PD risk has therefore been unclear, although a recent study proposed variants in KANSL1 as underlying this association by altering mitophagy 32 . In contrast, we did not find any effect of our PD- associated H1 sub-haplotypes on either KANSL1 expression or copy number, but did observe a consistent association with the expression of another gene in the locus, LRRC37A/2 .…”

Section: Discussionmentioning

confidence: 99%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh

Liu

et al. 2019

Preprint

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Parkinson's disease (PD) and progressive supranuclear palsy (PSP) are clinically similar neurodegenerative movement disorders that display unique neuropathological features (i.e. Lewy body pathology and Tau pathology, respectively). While each disorder has distinct clinical and genetic risk factors, both are associated with the MAPT 17q.21.31 locus H1 haplotype. This suggests a pleiotropic effect of this genomic region. To better understand the genetic contribution of this region to these diseases, we fine-mapped the apparent pleiotropy of this locus. Our study indicates that PD and PSP are associated with different sub-haplotypes of the H1 clade. PDassociated sub-haplotypes were associated with altered LRRC37A copy number and expression, which, like other PD risk-associated genes, we hypothesize to be most relevant to astroglial function. In contrast, PSP was associated with grossly altered LD structure across the 17q21.31 locus, and risk-associated variants were found to impact chromatin structure in both neurons and microglia. We conclude that the contribution of the 17q21.31 locus to multiple disorders is a result of its structural and haplotypic complexity, which in turn impacts the regulation of multiple genes and neural cell types. This raises the possibility of novel disease-specific pathogenic mechanisms driven by 17q21.31 structural variation and altered epigenetic regulation that appear to converge on glial function and gene expression. By fine-mapping the association of H1 with PD and PSP, we have begun to untangle the apparent pleiotropy of this locus, and gain better insight into the mechanism of each disease, which will guide future functional analyses and disease models for PD and PSP.

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“…Furthermore, while tau pathology can occur alongside α-synuclein inclusions in the substantia nigra [16,17], it is not a typical neuropathological feature of PD [15]. The causal gene underlying the genetic association across the 17q21.31 locus with PD risk has therefore been unclear, although a recent study proposed that H1-associated variants in KANSL1 alter mitophagy [40]. In contrast, we did not find any effect of our PD-associated H1 subhaplotypes on either KANSL1 expression or copy number, but did observe a consistent association with the expression of another gene in the locus, LRRC37A/2.…”

Section: Discussionmentioning

confidence: 99%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh²,

Liu³

et al. 2022

Mol Neurodegeneration

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Background Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. Methods To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. Results We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. Conclusion These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

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Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at Chr16q11.2 and on the MAPT H1 allele

Cited by 8 publications

References 51 publications

APOE and MAPT Are Associated With Dementia in Neuropathologically Confirmed Parkinson's Disease

APOE and MAPT Are Associated With Dementia in Neuropathologically Confirmed Parkinson's Disease

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

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