- ISSN: 1871-5273
- E-ISSN: 1996-3181
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oa A Putative Role for the BCL2 Family of Proteins in the Pathophysiology of ALS
- Source: CNS & Neurological Disorders - Drug Targets, Volume 25, Issue 1, Jan 2026, p. 67 - 76
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- 10 Jul 2025
- 26 Aug 2025
- 23 Sep 2025
Abstract
Although motor neuron inclusions that contain hyperphosphorylated TDP-43 protein (p-TDP-43) are considered an important clue in the pathophysiology of ALS, the main determinants of the neuronal dysfunction remain unknown.
The spinal cords and motor cortex of 17 people (n=60 tissues) who died of ALS, with 10 controls were tested for p-TDP-43/neurofibrillary tangles (NFTs), biomarkers of neuroinflammation (GFAP, TMEM 119, miR-155, IL6, TNFα, IL1β, NF-κβ), neurodegeneration (NeuN, myelin basic protein) and BCL2 family proteins (BCL2, BCLW, BCLXL, and MCL1 each pro-survival as well as BIM, PUMA, NOXA, BAK, BAX each anti-survival) using in situ based methods including immunohistochemistry.
p-TDP-43 detection was strongly correlated with neuroinflammation and neurodegeneration in both humans and in a mouse model of ALS with the mutant human TDP-43 gene (B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J). The expression of each BCL2 family protein was significantly increased compared to the controls and co-localized with p-TDP-43 in both human and mouse models.
To test whether altering BCL2 activity affects ALS pathophysiology, the FDA-approved drug venetoclax, which blocks BCL2, was started at age 3 mo IP in these mice and prevented clinical motor neuron dysfunction (n=5), whereas the untreated littermates (n=4) each died of end-stage paralysis at 5-7 mo. Blocking Bcl2 in the ALS mice reduced neurodegeneration 5-fold and neuroinflammation by 81%.
It is concluded that: 1) dysregulation of BCL2 family proteins is implicated in ALS, and 2) blocking Bcl2 alone in the mouse ALS model can markedly reduce the neurodegeneration.
