Genetic insights into immune mechanisms of Alzheimer’s and Parkinson’s disease

Frontiers in Immunology

Immunology

Inge R. Holtman¹  Alexi Nott² 

[1] Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands;Department of Brain Sciences, Imperial College London, London, United Kingdom;UK Dementia Research Institute, Imperial College London, London, United Kingdom;

关键词: microglia;    immune;    Alzheimer’s disease;    Parkinson’s disease;    GWAS - genome-wide association study;    epigenetics;    genetics;   

DOI  :  10.3389/fimmu.2023.1168539

 received in 2023-02-17, accepted in 2023-04-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

Microglia, the macrophages of the brain, are vital for brain homeostasis and have been implicated in a broad range of brain disorders. Neuroinflammation has gained traction as a possible therapeutic target for neurodegeneration, however, the precise function of microglia in specific neurodegenerative disorders is an ongoing area of research. Genetic studies offer valuable insights into understanding causality, rather than merely observing a correlation. Genome-wide association studies (GWAS) have identified many genetic loci that are linked to susceptibility to neurodegenerative disorders. (Post)-GWAS studies have determined that microglia likely play an important role in the development of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The process of understanding how individual GWAS risk loci affect microglia function and mediate susceptibility is complex. A rapidly growing number of publications with genomic datasets and computational tools have formulated new hypotheses that guide the biological interpretation of AD and PD genetic risk. In this review, we discuss the key concepts and challenges in the post-GWAS interpretation of AD and PD GWAS risk alleles. Post-GWAS challenges include the identification of target cell (sub)type(s), causal variants, and target genes. Crucially, the prediction of GWAS-identified disease-risk cell types, variants and genes require validation and functional testing to understand the biological consequences within the pathology of the disorders. Many AD and PD risk genes are highly pleiotropic and perform multiple important functions that might not be equally relevant for the mechanisms by which GWAS risk alleles exert their effect(s). Ultimately, many GWAS risk alleles exert their effect by changing microglia function, thereby altering the pathophysiology of these disorders, and hence, we believe that modelling this context is crucial for a deepened understanding of these disorders.

【 授权许可】

Unknown   
Copyright © 2023 Nott and Holtman