Objective: To analyze the adult neurogenic response to a neurodegenerative process due to H-ABC tubulinopathy.

Background: H-ABC is a neurodegenerative disease caused by mutations in TUBB4A, characterized by hypomyelination and brain malformations. Clinically, it shows motor development delay, pyramidal and extrapyramidal movements, ataxia, spasticity, and cognitive and sensory deficits. Under physiological conditions, neural stem cells (NSCs) of the adult brain’s subventricular zone (SVZ) can generate new neurons and oligodendrocytes capable of migration.  Neurogenic activity has also been observed after some pathological processes. Taiep rat carries a mutation in TUBB4A, representing an excellent model for studying this disease and the neurogenic response to the neurodegenerative process.

Method: To detect cell proliferation in the SVZ, we injected taiep rats and WT control animals with Bromodeoxyuridine (BrdU, 200 mg/kg IP) at 3 and 6 months. After 12 hours, animals were transcardially perfused, the brain removed, and processed for fluorescence immunohistochemistry. We used antibodies against BrdU, GFAP, PLP, Neurofilaments, and myelin. Brain images were acquired with a confocal microscope and processed offline.

Results: We found hyperplasia of the SVZ in the H-ABC model observed as a thicker band of proliferative cells in the neurogenic region. Specifically, increased proliferative activity was confirmed by the BrdU signal in the mutant when compared to WT controls. Corpus callosum and cerebellum in taiep showed severe demyelination, confirming previous results. In these regions, there is also astrocytosis, which could indicate a reaction to the degenerative process and a high rate of proliferative cells to the astroglial line. 

Conclusion: H-ABC degeneration promotes reactive neurogenesis in the adult brain. We propose two possible hypotheses to these changes, i.e., some of the regulatory signaling pathways involved in the neurogenic processes could be disrupted in TUBB4A expressing cells. Alternatively, the tubulin mutation blocks the ability of new cells to migrate to their destination, inducing an accumulation of cells in the neurogenic region of the SVZ. The characteristic malformations observed in this disease could be due to the cell’s inability to migrate during development successfully.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hab-c-murine-model-present-reactive-adult-neurogenesis-and-astrogliosis-in-adult-brain/