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Reduced acetylated alpha-tubulin in SPAST hereditary spastic paraplegia patient PBMCs


HSP-SPAST is the most common form of hereditary spastic paraplegia (HSP), a neurodegenerative disease causing lower limb spasticity. Previous studies using HSP-SPAST patient-derived induced pluripotent stem cell cortical neurons have shown that patient neurons have reduced levels of acetylated alpha-tubulin, a form of stabilized microtubules, leading to a chain of downstream effects eventuating in increased vulnerability to axonal degeneration. Noscapine treatment rescued these downstream effects by restoring the levels of acetylated alpha-tubulin in patient neurons. Here we show that HSP-SPAST patient non-neuronal cells, peripheral blood mononuclear cells (PBMCs), also have the disease-associated effect of reduced levels of acetylated alpha-tubulin. Evaluation of multiple PBMC subtypes showed that patient T cell lymphocytes had reduced levels of acetylated alpha-tubulin. T cells make up to 80% of all PBMCs and likely contributed to the effect of reduced acetylated alpha-tubulin levels seen in overall PBMCs. We further showed that mouse administered orally with increasing concentrations of noscapine exhibited a dose-dependent increase of noscapine levels and acetylated alpha-tubulin in the brain. A similar effect of noscapine treatment is anticipated in HSP-SPAST patients. To measure acetylated alpha-tubulin levels, we used a homogeneous time resolved fluorescence technology-based assay. This assay was sensitive to noscapine-induced changes in acetylated alpha-tubulin levels in multiple sample types. The assay is high throughput and uses nano-molar protein concentrations, making it an ideal assay for evaluation of noscapine-induced changes in acetylated alpha-tubulin levels. This study shows that HSP-SPAST patient PBMCs exhibit disease-associated effects. This finding can help expedite the drug discovery and testing process.

Type Journal
ISBN 1662-4548 (Print) 1662-453X (Electronic) 1662-453X (Linking)
Authors Wali, G.; Siow, S. F.; Liyanage, E.; Kumar, K. R.; Mackay-Sim, A.; Sue, C. M.
Publisher Name Front Neurosci
Published Date 2023-03-31
Published Volume 17
Published Pages 1073516
Status Published in-print
DOI 10.3389/fnins.2023.1073516
URL link to publisher's version