{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:14:54Z","timestamp":1791598494746,"version":"4.3.4"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T00:00:00Z","timestamp":1679961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>HSP<jats:italic>-SPAST<\/jats:italic> is the most common form of hereditary spastic paraplegia (HSP), a neurodegenerative disease causing lower limb spasticity. Previous studies using HSP<jats:italic>-SPAST<\/jats:italic> patient-derived induced pluripotent stem cell cortical neurons have shown that patient neurons have reduced levels of acetylated \u03b1-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 \u03b1-tubulin in patient neurons. Here we show that HSP<jats:italic>-SPAST<\/jats:italic> patient non-neuronal cells, peripheral blood mononuclear cells (PBMCs), also have the disease-associated effect of reduced levels of acetylated \u03b1-tubulin. Evaluation of multiple PBMC subtypes showed that patient T cell lymphocytes had reduced levels of acetylated \u03b1-tubulin. T cells make up to 80% of all PBMCs and likely contributed to the effect of reduced acetylated \u03b1-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 \u03b1-tubulin in the brain. A similar effect of noscapine treatment is anticipated in HSP-<jats:italic>SPAST<\/jats:italic> patients. To measure acetylated \u03b1-tubulin levels, we used a homogeneous time resolved fluorescence technology-based assay. This assay was sensitive to noscapine-induced changes in acetylated \u03b1-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 \u03b1-tubulin levels. This study shows that HSP-<jats:italic>SPAST<\/jats:italic> patient PBMCs exhibit disease-associated effects. This finding can help expedite the drug discovery and testing process.<\/jats:p>","DOI":"10.3389\/fnins.2023.1073516","type":"journal-article","created":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T04:24:34Z","timestamp":1679977474000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Reduced acetylated \u03b1-tubulin in SPAST hereditary spastic paraplegia patient PBMCs"],"prefix":"10.3389","volume":"17","author":[{"given":"Gautam","family":"Wali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue-Faye","family":"Siow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erandhi","family":"Liyanage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kishore R.","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Mackay-Sim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M.","family":"Sue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1242\/dmm.010884","article-title":"A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations","volume":"6","author":"Abrahamsen","year":"2013","journal-title":"Dis. 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