Advances in the discovery of genetic risk factors for complex forms of neurodegenerative disorders: contemporary approaches, success, challenges and prospects

Journal of genetics

SUMEET KUMAR^1¹  NAVNEESH YADAV^1² 

[1] Department of Genetics, University of Delhi South Campus, New Delhi 110 021, India^1;Department of Neurology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi 110 002, India^2

关键词: neurodegenerative disorders;    Alzheimer’s disease;    Parkinson’s disease;    amyotrophic lateral sclerosis;    Huntington disease;    genomewide association studies;   

DOI  :  

学科分类：生物科学（综合）

来源: Indian Academy of Sciences

【 摘 要 】

Neurodegenerative diseases constitute a large proportion of disorders in elderly, majority being sporadic in occurrence with ∼5–10% familial. A strong genetic component underlies the Mendelian forms but nongenetic factors together with genetic vulnerability contributes to the complex sporadic forms. Several gene discoveries in the familial forms have provided novel insights into the pathogenesis of neurodegeneration with implications for treatment. Conversely, findings from genetic dissection of the sporadic forms, despite large genomewide association studies and more recently whole exome and whole genome sequencing, have been limited. This review provides a concise account of the genetics that we know, the pathways that they implicate, the challengesthat are faced and the prospects that are envisaged for the sporadic, complex forms of neurodegenerative diseases, taking four most common conditions, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington disease as examples. Poor replication across studies, inability to establish genotype–phenotype correlations and the overall failure to predictrisk and/or prevent disease in this group poses a continuing challenge. Among others, clinical heterogeneity emerges as the most important impediment warranting newer approaches. Advanced computational and system biology tools to analyse the big data are being generated and the alternate strategy such as subgrouping of case–control cohorts based on deep phenotyping using theprinciples of Ayurveda to overcome current limitation of phenotype heterogeneity seem to hold promise. However, at this point, with advances in discovery genomics and functional analysis of putative determinants with translation potential for the complex forms being minimal, stem cell therapies are being attempted as potential interventions. In this context, the possibility to generatepatient derived induced pluripotent stem cells, mutant/gene/genome correction through CRISPR/Cas9 technology and repopulating the specific brain regions with corrected neurons, which may fulfil the dream of personalized medicine have been mentioned briefly. Understanding disease pathways/biology using this technology, with implications for development of novel therapeutics are optimisticexpectations in the near future.

【 授权许可】

CC BY