MAPT Genetic Variation and Neuronal Maturity Alter Isoform Expression Affecting Axonal Transport in iPSC-Derived Dopamine Neurons

Beevers, Joel E.; Lai, Mang Ching; Collins, Emma; Booth, Heather; Zambon, Federico; Parkkinen, Laura; Vowles, Jane; Cowley, Sally A.; Wade‐Martins, Richard; Caffrey, Tara M.

doi:10.1016/j.stemcr.2017.06.005

Cited by 47 publications

(38 citation statements)

References 37 publications

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“…The MAPT locus, found on chromosome 17, represents one of the largest LD blocks in the human genome (1.8 Mb) and is present in two distinct haplotypes, H1 and H2, the latter formed by an approximately 900 kb inversion of H1 that occurred about 3 million years ago and is present mostly in Europeans 51 . Cumulatively, previous work supports MAPT haplotype-specific impacts on transcript amount, transcript stability, and alternative splicing in several neurodegenerative disorders 54, 56, 57 . We highlight multiple epigenetic avenues through which the MAPT gene is differentially regulated in the H1 and H2 haplotypes, thus explaining at least a portion of the molecular underpinnings of the observed MAPT GWAS association in PD.…”

Section: Discussionmentioning

confidence: 54%

Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

Corces

Shcherbina

Kundu

et al. 2020

Preprint

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42Genome-wide association studies (GWAS) have identified thousands of variants associated with 43 disease phenotypes. However, the majority of these variants do not alter coding sequences, making 44 it difficult to assign their function. To this end, we present a multi-omic epigenetic atlas of the 45 adult human brain through profiling of the chromatin accessibility landscapes and three-46 dimensional chromatin interactions of seven brain regions across a cohort of 39 cognitively healthy 47 individuals. Single-cell chromatin accessibility profiling of 70,631 cells from six of these brain 48 regions identifies 24 distinct cell clusters and 359,022 cell type-specific regulatory elements, 49 capturing the regulatory diversity of the adult brain. We develop a machine learning classifier to 50 integrate this multi-omic framework and predict dozens of functional single nucleotide 51 polymorphisms (SNPs), nominating gene and cellular targets for previously orphaned GWAS loci. 52These predictions both inform well-studied disease-relevant genes, such as BIN1 in microglia for 53 Alzheimer's disease (AD) and reveal novel gene-disease associations, such as STAB1 in microglia 54 and MAL in oligodendrocytes for Parkinson's disease (PD). Moreover, we dissect the complex 55 inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying ectopic enhancer-gene 56 contacts in neurons that increase MAPT expression and may mediate this disease association. This 57 work greatly expands our understanding of inherited variation in AD and PD and provides a 58 roadmap for the epigenomic dissection of noncoding regulatory variation in disease. 59 60 61 62Alzheimer's disease (AD) and Parkinson's disease (PD) affect ~50 and ~10 million individuals 63 world-wide, as two of the most common neurodegenerative disorders. Several large consortia have 64 assembled genome-wide association studies (GWAS) that associate genetic variants with clinical 65 diagnoses of probable AD dementia 1-4 or probable PD 5-7 , or with their characteristic pathologic 66 features. These efforts have led to the identification of dozens of potential risk loci for these 67 prevalent neurodegenerative diseases. One goal of these studies was to build more precise 68 molecular biomarkers of AD or PD, efforts that are beginning to yield encouraging results with 69 polygenic risk scores 8 . The other major goal was to gain deeper insight into the molecular 70 pathogenesis of disease and thereby inform novel therapeutic targets. Some of the risk loci contain 71 coding variants and so have credibility as putative disease mediators. However, most risk loci are 72 in noncoding regions and so it remains unclear if the nominated (often nearest) gene is the 73 functional disease-relevant gene, or if some other gene is involved 9 . Furthermore, even if the 74 nominated gene is a true positive, the noncoding risk locus might regulate additional genes. These 75 challenges remain a fundamental gap in interpreting the etiology of neurodegenerative diseases 76 and d...

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Section: Discussionmentioning

confidence: 54%

Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

Corces

Shcherbina

Kundu

et al. 2020

Preprint

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“…47–52 The MAPT H1 haplotype has been shown to alter the axonal transport velocities of mitochondria, providing a biological connection to 2 of our most interesting genetic signals. 39 …”

Section: Discussionmentioning

confidence: 99%

Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

et al. 2018

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IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood.OBJECTIVES To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. DESIGN, SETTING, AND PARTICIPANTSIn this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. MAIN OUTCOMES AND MEASURESThe primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. RESULTS Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002

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“…Overall neuronal metabolism may be impaired by endogenous dysfunction of mitochondria 25,31,[37][38][39]52,55,57,59,61,64,67,68,70,73,74,77,85,89,90 , or indirect external stressors 24,32,62,71,90 , or by abnormal recycling of damaged mitochondria 38,39,52,68 . For example, some patient neurons displayed signs of impaired mitochondrial quality control related to aberrant mitophagy 38,52,68 , mitochondrial DNA damage 37,57 and consistent decreases in mitochondrial membrane potential 24,38,67,83,85 .…”

Section: How Environmental Factors and Aging Can Be Recapitulated Inmentioning

confidence: 99%

“…Genetic predispositions increase the probability of protein aggregation in PD neurons Alpha-synuclein and Tau protein accumulation constitute the most common phenotype reported in 28 studies investigating LRRK2, PRKN, PINK1, GBA, SNCA, and MAPT lines [25][26][27][28][29][30][31][34][35][36]39,41,43,46,[48][49][50][51]53,55,56,58,60,65,67,69,73,83 . The upregulation MAPT (microtubule-associated protein tau) transcripts were associated with protein aggregation, which impaired axonal mitochondria movement and induced neurite aberrations in patient neurons 25,53,213 . The accumulation of α-synuclein and Tau has also been noted in the varicosities of contorted and fragmented axons of patients 41 .…”

Section: How Environmental Factors and Aging Can Be Recapitulated Inmentioning

confidence: 99%

Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells

Tran

Anastacio

Bardy

2020

npj Parkinsons Dis.

111

103

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Parkinson's disease (PD) is the second most prevalent neurological disorder and has been the focus of intense investigations to understand its etiology and progression, but it still lacks a cure. Modeling diseases of the central nervous system in vitro with human induced pluripotent stem cells (hiPSC) is still in its infancy but has the potential to expedite the discovery and validation of new treatments. Here, we discuss the interplay between genetic predispositions and midbrain neuronal impairments in people living with PD. We first summarize the prevalence of causal Parkinson's genes and risk factors reported in 74 epidemiological and genomic studies. We then present a meta-analysis of 385 hiPSC-derived neuronal lines from 67 recent independent original research articles, which point towards specific impairments in neurons from Parkinson's patients, within the context of genetic predispositions. Despite the heterogeneous nature of the disease, current iPSC models reveal converging molecular pathways underlying neurodegeneration in a range of familial and sporadic forms of Parkinson's disease. Altogether, consolidating our understanding of robust cellular phenotypes across genetic cohorts of Parkinson's patients may guide future personalized drug screens in preclinical research.

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MAPT Genetic Variation and Neuronal Maturity Alter Isoform Expression Affecting Axonal Transport in iPSC-Derived Dopamine Neurons

Cited by 47 publications

References 37 publications

Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells

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