A novel innate immunity risk factor for amyotrophic lateral sclerosis

Project: Research project

Project Details

Description

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, 20% of ALS cases are genetic, with monogenic causes identified in about 17 % or so. The remaining 80% of cases appear to be multifactorial, and no reproducible and/or robust genetic association or environmental factor(s), internal or external, has been identified. Although the role of innate immunity has been explored and some innate immunity factors highlighted, their role as initiators, amplifiers or secondary markers of an ongoing inflammatory response is not established. As the result of our study of gene variants of cargo proteins of the HDL particle we identified the trypanocide blood and CSF protein, Apol1, as a promising agent affecting ALS that is also sensitive to environmental factors ApoL1 is a secreted innate immunity factor carried by the high-density lipoprotein particle HDL3 and CSF. ApoL1 forms a channel in the lysosomal membrane and disrupts the blood borne parasite’s lysosomal function, killing it. For most trypanasome exposures, this process is clinically inapparent because only two of the twenty known trypanosome species, T.brucei and its varieties and T.cruzei, are pathogenic to humans. Variant alleles of APOL1 emerged in Africa with the property of antagonistic pleiotropy, effective against resistant strains of T.brucei, they cause progressive kidney disease especially in SLE and AIDS {}. In vitro Apol1 causes autophagic cell death in cancer cells. {}. We examined the association of selected genetic variants of APOL1 and the concentration of the Apol1 protein in control and ALS plasma. In our initial study of 300 cases and 300 controls three variants were associated with SALS, while plasma ApoL1 levels were significantly different between controls and cases (p=0.03). A highly skewed profile of the upper quartile (p=0001) between controls and ALS cases was noted. Our hypothesis is that APOL1 variants are associated with ALS because elevated Apol1 levels in plasma and or CSF are toxic to certain neurons. Apol1 levels are and influenced by in cis or in trans factors. Apol1 is likely regulated in cis by gene expression variants and/or by in tran due to exposure to trypanosomes or to cytokines such as the interferons or other, yet to be identified, factors. Humans and a few other primates have the APOL1 gene, while rodents and other mammals do not. Antagonistic pleiotropy of some APOL1 allelic variants may thus be protective against most trypanosomes but possibly detrimental in neurodegeneration.
Innovation: This is a novel pioneering effort to ascertain 1. Whether APOL1 genetic variants and Apol1 levels predispose to SALS. 2. The extent to Apol1 levels are affected by in cis and possibly in trans genetic expression variants like eQTLs. 3. The effect on Apol1 levels by in trans environmental factors of exposure to trypanosomes, or secondarily by cytokines such as TNF-α, γ-interferon and type 1 interferons, or a combination thereof. 4. To establish Apol1 in the pathology of vulnerable neurons in human ALS. Our promising preliminary data, experienced team and rigorously defined cohort of age matched ALS cases and controls and extensive collection of ALS tissue and ongoing environment exposure data puts us in a unique position to carry out this novel proposal to fundamentally affect the understanding of SALS and its treatment
Aim 1. Determine in cis variants in the region of APOL1 gene for association to ALS and endophenotypes in our existing SALS patients and control samples (750 each) using custom capture targeted high throughput sequ
StatusActive
Effective start/end date9/1/198/31/22

Funding

  • Agency for Toxic Substances and Disease Registry (5R01TS000294-02-00)

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