# A novel innate immunity risk factor for amyotrophic lateral sclerosis

> **NIH ALLCDC R01** · NORTHWESTERN UNIVERSITY · 2021 · $299,999

## Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. 20% of ALS cases are genetic,
with monogenic causes identified in about 17%. The remaining 80% of cases appear to be multifactorial, and
no reproducible and/or robust genetic association or environmental factor(s), internal or external, have 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 in ALS. As the result of our study of gene variants of cargo proteins of the HDL particle, we
identified the trypanocidal 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 HDL3and CSF. APOL1 forms a channel in the lysosomal membrane and disrupts the blood
borne parasite's lysosomal function, killing it. Most trypanasome exposures are clinically inapparent because
only two of the twenty known trypanosome species, varieties of T.brucei and T.cruzei, are pathogenic to
humans. Variant alleles of looAPOL1 emerged in Africa with the property of antagonistic pleiotropy, effective
against resistant strains of T.brucei, but they can cause progressive kidney disease especially with SLE and
AIDS as co-morbities. Our hypothesis is that some APOL1 variants are associated with ALS because elevated
APOL1 levels in plasma and or CSF can be toxic to susceptible neurons. APOL1 levels are influenced by in
cis or in trans factors. APOL1 gene expression is likely regulated in cis by specific DNA variants and/or by in
trans due to exposure to trypanosomes or to cytokines such as the interferons or other, yet to be identified,
environmental factors. We have patient samples with associated epidemiological data that we will use to
determine which APOL1 variants are correlated with plasma concentrations of ApoL1 and/or mRNA expression
in patient-derived lymphoblasts. We also will additional patient and control samples from our own collection
and those collected prospectively from new patients. In selected samples we will run assays to determine if
blood can be used to determine whether a prior trypansomal infection has occurred as well as levels of
cytokines that may be elevated due to inflammatory responses related to infection.
This is a novel pioneering effort to ascertain 1. Whether APOL1 genetic variants and APOL1 levels predispose
to SALS. 2. The extent to which Apol1 levels are affected by in cis and possibly in trans genetic variantsacting
as 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 rig...

## Key facts

- **NIH application ID:** 10220811
- **Project number:** 5R01TS000294-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** TEEPU SIDDIQUE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** ALLCDC
- **Fiscal year:** 2021
- **Award amount:** $299,999
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220811

## Citation

> US National Institutes of Health, RePORTER application 10220811, A novel innate immunity risk factor for amyotrophic lateral sclerosis (5R01TS000294-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10220811. Licensed CC0.

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