Knockdown of Unconventional Myosin ID Expression Induced Morphological Change in Oligodendrocytes

Yamazaki, Reiji; Ishibashi, Tomoko; Baba, Hiroko; Yamaguchi, Yoshihide

doi:10.1177/1759091416669609

Cited by 12 publications

(5 citation statements)

References 51 publications

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“…However, PLP1 has been implicated in both OPC migration 26 and as a bridge between the membrane and cytoskeleton. 66 It is possible that, in the absence of PLP1, cell processes become insensitive to stimuli that would normally trigger them to extend. Similarly, observed deficits in distal branching could be secondary to failed process extension or result from loss of PLP1's structural cytoskeletal support.…”

Section: Discussionmentioning

confidence: 99%

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Nevin

Factor

Karl

et al. 2017

The American Journal of Human Genetics

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Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD-including point mutations and duplication, triplication, and deletion of PLP1-and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.

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Section: Discussionmentioning

confidence: 99%

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Nevin

Factor

Karl

et al. 2017

The American Journal of Human Genetics

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“…48 Despite its apparent sex-specificity previous work has nominated MYOD1 as a potential drug target for AD according to predictive network analysis. 49,50 The encoded protein, myogenic differentiation 1, is involved in myelin sheath formation 51 and both common 52 and rare 53 variants have been associated with autism, supporting MYO1D's role in neural development and functioning.…”

Section: Discussionmentioning

confidence: 99%

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Neumann

Ohlei

Küçükali

et al. 2022

Preprint

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Genome-wide association studies (GWAS) of Alzheimer′s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to: 1. identify common genetic variants associated with these CSF profiles; 2. assess the role of associated variants in AD pathophysiology and 3. explore potential sex differences. We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n=205 controls, n=546 mild cognitive impairment, n=222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested, whether biomarker PCs mediate SNP risk effects on AD, and stratified and interaction models probed sex-specific effects. Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 and GRIN2D) and three were previously described (APOE, TMEM160B and CHI3L). GRIN2D was associated with synaptic functioning, whereas rs145791381 was associated with biomarker evidence of inflammation. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. The results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

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“…Despite its apparent sex-specificity previous work has nominated MYOD1 as a potential drug target for AD according to predictive network analysis [ 57 , 58 ]. The encoded protein, myogenic differentiation 1, is involved in myelin sheath formation [ 59 ] and both common [ 60 ] and rare [ 61 ] variants have been associated with autism, supporting MYO1D ’s role in neural development and functioning.…”

Section: Discussionmentioning

confidence: 99%

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Neumann,

Ohlei,

Küçükali

et al. 2023

Genome Med

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Background Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. Methods We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Results Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. Conclusions These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

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Knockdown of Unconventional Myosin ID Expression Induced Morphological Change in Oligodendrocytes

Cited by 12 publications

References 51 publications

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

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