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Modeling spastic paraplegia 4 with corticospinal motor neuron-enriched cortical organoids reveals genotype-phenotype and HDAC6-targetable pathology
Journal article   Open access   Peer reviewed

Modeling spastic paraplegia 4 with corticospinal motor neuron-enriched cortical organoids reveals genotype-phenotype and HDAC6-targetable pathology

Neha Mohan, Skandha Ramakrishnan, Xiaohuan Sun, Ying Sun, Theresa Connors, Victor Chai, Emanuela Piermarini, Peter W Baas, James Cai, Mei Liu, …
Cell reports (Cambridge), v 45(3), 117036
24 Feb 2026
PMID: 41739645
url
https://doi.org/10.1016/j.celrep.2026.117036View
Published, Version of Record (VoR) Open

Abstract

human induced pluripotent stem cells CP: neuroscience spastin SPAST histone deacetylase 6 CP: stem cell research cortical organoids microtubule acetylation spastic paraplegia 4 corticospinal motor neurons tubastatin A
Spastic paraplegia 4 (SPG4), the most common form of hereditary spastic paraplegia, causes progressive gait deficiency due to corticospinal tract degeneration. SPG4 results from mutations in the SPAST gene, which encodes spastin, a microtubule-severing AAA-ATPase. To dissect genotype-phenotype relationships, we generated isogenic human induced pluripotent stem cell lines carrying either an SPAST missense (SPAST ) or truncation (SPAST ) mutation and differentiated them into corticospinal motor neuron-enriched cortical organoids. These models revealed mutation-specific patterns of aberrant neuronal activity, microtubule hypoacetylation, and axonal degeneration. We identified mutant M1-spastin-induced hyperactivation of histone deacetylase 6 (HDAC6), a major tubulin deacetylase, as the key pathogenic culprit. Pharmacological inhibition of HDAC6 with tubastatin A restored microtubule acetylation and rescued axonal degeneration in organoids, with corresponding improvements in corticospinal tract integrity and gait defects in SPG4 transgenic mice. Our study uncovers HDAC6 hyperactivation as a targetable mechanism for SPG4 and verifies human organoids as a platform for therapeutic discovery.

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