Modeling spastic paraplegia 4 with corticospinal motor neuron-enriched cortical organoids reveals genotype-phenotype and HDAC6-targetable pathology - PubMed
5 hours ago
- #HDAC6
- #SPG4
- #organoids
- Study models Spastic Paraplegia 4 (SPG4) using corticospinal motor neuron-enriched cortical organoids.
- SPG4 is caused by mutations in the SPAST gene, leading to corticospinal tract degeneration.
- Isogenic human iPSC lines with SPAST mutations (C448Y, S245X) were generated for the study.
- Organoids showed mutation-specific patterns of neuronal dysfunction, microtubule hypoacetylation, and axonal degeneration.
- HDAC6 hyperactivation was identified as a key pathogenic mechanism in SPG4.
- HDAC6 inhibition with tubastatin A restored microtubule acetylation and improved axonal degeneration in organoids.
- Therapeutic benefits of HDAC6 inhibition were also observed in SPG4 transgenic mice.