Emerging insights into the complex genetics and pathophysiology of ALS

Details

• Alternative Title:
  Lancet Neurol
• Personal Author:
  Goutman, Stephen A ; Hardiman, Orla ; Al-Chalabi, Ammar ; Chió, Adriano ; Savelieff, Masha G ; Kiernan, Matthew C. ; Feldman, Eva L
• Description:
  Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. The discovery of genes associated with amyotrophic lateral sclerosis, commencing with SOD1 in 1993, started fairly gradually. Recent advances in genetic technology have led to the rapid identification of multiple new genes associated with the disease, and to a new understanding of oligogenic and polygenic disease risk. The overlap of genes associated with amyotrophic lateral sclerosis with those of other neurodegenerative diseases is shedding light on the phenotypic spectrum of neurodegeneration, leading to a better understanding of genotype-phenotype correlations. A deepening knowledge of the genetic architecture is allowing the characterisation of the molecular steps caused by various mutations that converge on recurrent dysregulated pathways. Of crucial relevance, mutations associated with amyotrophic lateral sclerosis are amenable to novel gene-based therapeutic options, an approach in use for other neurological illnesses. Lastly, the exposome-the summation of lifetime environmental exposures-has emerged as an influential component for amyotrophic lateral sclerosis through the gene-time-environment hypothesis. Our improved understanding of all these aspects will lead to long-awaited therapies and the identification of modifiable risks factors.
• Keywords:
  Amyotrophic Lateral Sclerosis Environmental Exposure Exposome Gene Therapy Genetic Architecture Genetic Association Studies Humans Motor Neuron Disease Mutation Neurodegenerative Diseases Pathophysiology

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• Source:
  Lancet Neurol. 21(5):465-479
• Pubmed ID:
  35334234
• Pubmed Central ID:
  PMC9513754
• Document Type:
  Journal Article
• Funding:
  AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease AssociationUnited Kingdom/ ; R01TS000289/ACL/ACL HHSUnited States/ ; R01 TS000327/TS/ATSDR CDC HHSUnited States/ ; K23 ES027221/ES/NIEHS NIH HHSUnited States/ ; MR/L501529/1/MRC_/Medical Research CouncilUnited Kingdom/ ; R01 ES030049/ES/NIEHS NIH HHSUnited States/ ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease AssociationUnited Kingdom/ ; R01 NS120926/NS/NINDS NIH HHSUnited States/ ; R01 NS127188/NS/NINDS NIH HHSUnited States/ ; MR/R024804/1/MRC_/Medical Research CouncilUnited Kingdom/ ; R01 TS000289/TS/ATSDR CDC HHSUnited States/
• Volume:
  21
• Issue:
  5
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:9c764d3c44238fcfe089a2ca320c1bf4ddeb37f5ec9e58e4ccb98182c6e06716
• Download URL:
  https://stacks.cdc.gov/view/cdc/121574/cdc_121574_DS1.pdf
• File Type:
  [PDF - 1.46 MB ]