Update on genetics of amyotrophic lateral sclerosis DOI
Dávid Brenner, Axel Freischmidt

Current Opinion in Neurology, Journal Year: 2022, Volume and Issue: 35(5), P. 672 - 677

Published: Aug. 8, 2022

Purpose of review ALS genetics are highly dynamic and great interest for the research community. Each year, by using ever-growing datasets cutting-edge methodology, an array novel ALS-associated genes downstream pathomechanisms discovered. The increasing plenty complexity insights warrants regular summary by-reviews. Recent findings Most recent disease gene discoveries constitute candidate risk SPTLC1 , KANK1 CAV1 HTT WDR7 as well seven loci. Cell type functional enrichment analyses enlighten genetic basis selective motor neuron vulnerability in demonstrating high expression cortical neurons highlight pathogenic significance cell-autonomous processes. Major pathomechanistic have been gained regarding known genes/proteins, specifically C9orf72 TDP43, ANXA11 KIF5A . first ASO-based gene-specific therapy trials familial forms yielded equivocal results stressing re-evaluation linked to SOD1 mutations. Summary molecular is increasingly examined on single-cell resolution. In past 2 years, understanding mechanisms several TDP-43 proteinopathy has considerably extended. These will result specific approaches sporadic subtypes.

Language: Английский

Cell subtype-specific effects of genetic variation in the Alzheimer’s disease brain DOI
Masashi Fujita,

Zongmei Gao,

Lu Zeng

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(4), P. 605 - 614

Published: March 21, 2024

Language: Английский

Citations

60
A concerted neuron–astrocyte program declines in ageing and schizophrenia DOI Creative Commons
Emi Ling,

James Nemesh,

Melissa Goldman

et al.

Nature, Journal Year: 2024, Volume and Issue: 627(8004), P. 604 - 611

Published: March 6, 2024

Abstract Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people’s cortical neurons astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22–97 years, including healthy individuals with schizophrenia. Latent-factor analysis these data revealed that, whose more strongly expressed genes encoding synaptic components, astrocytes distinct functions for synthesizing cholesterol, an astrocyte-supplied component membranes. call this neuron astrocyte program (SNAP). In schizophrenia ageing—two conditions that involve declines cognitive flexibility plasticity 1,2 —cells divested from SNAP: astrocytes, glutamatergic (excitatory) GABAergic (inhibitory) all showed reduced SNAP expression corresponding degrees. The astrocytic neuronal components both involved which genetic risk factors were concentrated. SNAP, varies quantitatively even among similar age, may underlie many aspects normal interindividual differences be important point convergence multiple kinds pathophysiology.

Language: Английский

Citations

53
Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis-regulatory elements DOI Creative Commons
Ashlyn G. Anderson, Brianne B. Rogers, Jacob M. Loupe

et al.

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(3), P. 100263 - 100263

Published: Feb. 2, 2023

Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer's disease (AD) and unaffected controls have been well documented, but few studies rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq plus snATAC-seq) on 105,332 nuclei isolated cortical 7 AD 8 to identify candidate

Language: Английский

Citations

50
Shared genetic risk loci between Alzheimer’s disease and related dementias, Parkinson’s disease, and amyotrophic lateral sclerosis DOI Creative Commons
Michael Wainberg, Shea J. Andrews, Shreejoy J. Tripathy

et al.

Alzheimer s Research & Therapy, Journal Year: 2023, Volume and Issue: 15(1)

Published: June 16, 2023

Genome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's (PD) amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific variants loci underlying this remain almost entirely unknown.

Language: Английский

Citations

47
Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery DOI Creative Commons
Satoru Morimoto, Shinichi Takahashi, Daisuke Ito

et al.

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(6), P. 766 - 780.e9

Published: June 1, 2023

iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received or placebo for 24 weeks the double-blind period evaluate safety, tolerability, and therapeutic effects. Adverse events were similar both groups. During period, muscle strength daily activity maintained, but decline ALSFRS-R, which assesses functional status patients, was not different from that group. However, open-label extension group showed significant suppression ALSFRS-R an additional 27.9 disease-progression-free survival. iPSC-derived motor neurons dopamine D2 receptor expression potential involvement SREBP2-cholesterol pathway Lipid peroxide represents clinical surrogate marker assess disease progression efficacy. Limitations include small sample sizes high attrition rates requiring further validation.

Language: Английский

Citations

42
Molecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases DOI
Martin Kampmann

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(5), P. 351 - 371

Published: April 4, 2024

Language: Английский

Citations

34
Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD DOI
S. Sebastian Pineda, Hyeseung Lee, María José Ulloa-Navas

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(8), P. 1971 - 1989.e16

Published: March 22, 2024

Language: Английский

Citations

32
Genetic architecture of the structural connectome DOI Creative Commons
Michael Wainberg, Natalie J. Forde,

Salim Mansour

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 4, 2024

Abstract Myelinated axons form long-range connections that enable rapid communication between distant brain regions, but how genetics governs the strength and organization of these remains unclear. We perform genome-wide association studies 206 structural connectivity measures derived from diffusion magnetic resonance imaging tractography 26,333 UK Biobank participants, each representing density myelinated within or a pair cortical networks, subcortical structures hemispheres. identify 30 independent significant variants after Bonferroni correction for number studied (126 at nominal significance) implicating genes involved in myelination ( SEMA3A ), neurite elongation guidance NUAK1 , STRN DPYSL2 EPHA3 HGF SHTN1 neural cell proliferation differentiation GMNC CELF4 neuronal migration CCDC88C cytoskeletal CTTNBP2 MAPT DAAM1 MYO16 PLEC metal transport SLC39A8 ). These have four broad patterns spatial with connectivity: some disproportionately strong associations corticothalamic connectivity, interhemispheric both, while others are more spatially diffuse. Structural highly polygenic, median 9.1 percent common estimated to non-zero effects on measure, exhibited signatures negative selection. genetic correlations variety neuropsychiatric cognitive traits, indicating connectivity-altering tend influence health function. Heritability is enriched regions increased chromatin accessibility adult oligodendrocytes (as well as microglia, inhibitory neurons astrocytes) multiple fetal types, suggesting control partially mediated by early development. Our results indicate pervasive, pleiotropic, structured white-matter via diverse neurodevelopmental pathways, support relevance this healthy

Language: Английский

Citations

20
Causal relationship between immune cells and neurodegenerative diseases: a two-sample Mendelian randomisation study DOI Creative Commons
Chao Tang,

Xiaoyang Lei,

Yaqi Ding

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 29, 2024

Background There is increasing evidence that the types of immune cells are associated with various neurodegenerative diseases. However, it currently unclear whether these associations reflect causal relationships. Objective To elucidate relationship between and diseases, we conducted a two-sample Mendelian randomization (MR) analysis. Materials methods The exposure outcome GWAS data used in this study were obtained from an open-access database ( https://gwas.mrcieu.ac.uk/ ), employed MR analysis to assess 731 cell features four including Alzheimer’s disease (AD), Parkinson’s (PD), amyotrophic lateral sclerosis (ALS) multiple (MS). All was Multiple minimize bias obtain reliable estimates variables interest outcomes. Instrumental variable selection criteria restricted ensure accuracy effectiveness species risk Results identified potential relationships different Specifically, found 8 have AD, 1 type has PD, 6 ALS, MS. Conclusion Our study, through genetic means, demonstrates close specific ALS MS, providing useful guidance for future clinical researches.

Language: Английский

Citations

19
Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS DOI
Paul J. Hop, Ramona A.J. Zwamborn, Eilís Hannon

et al.

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(633)

Published: Feb. 23, 2022

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures progression, well providing potential mechanism that mediates genetic or environmental risk. Here, we present blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified total 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways traits related metabolism, cholesterol biosynthesis, immunity. then tested 39 methylation–based putative ALS risk factors found high-density lipoprotein cholesterol, body mass index, white blood cell proportions, alcohol intake were independently associated ALS. Integration these results our latest genome-wide showed biosynthesis was potentially causally Last, at several DMPs proportion estimates derived from data survival rate suggesting they might represent indicators underlying processes amenable therapeutic interventions.

Language: Английский

Citations

66