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Abstract Details

Cellular models of Hypomyelination and Atrophy of Basal Ganglia and Cerebellum using rodent and human induced pluripotent stem cells
Child Neurology and Developmental Neurology
S51 - Child Neurology: Bench to Bedside: Progress in Treating Genetic Disorders (4:47 PM-4:58 PM)
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Gain of function mutations occurring in the cytoskeletal gene TUBB4A (tubulin beta 4A) lead to a spectrum of hypomyelinating leukodystrophies and isolated dystonia, including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC). H-ABC typically results from the most common TUBB4A mutation, p. Asp249Asn (D249N). Affected individuals exhibit dystonia, gait impairment and progressive neurologic decline. 

Establish the effect of TUBB4A mutations on neurons and oligodendrocytes using murine and human cells in culture.

To explore the underlying cellular contributions of TUBB4A mutations, we examined cell-autonomous effects in neurons and oligodendrocytes (OLs) in vitro from Tubb4aD249N/D249N mice and human induced pluripotent stem cells (iPSC) derived cultures. Murine neurons were assessed for survival, axonal length and microtubule dynamics using live cell imaging of EB3 comets. OLs were studied for expression of myelin proteins and complexity of arborization using Sholl analysis. Finally, to test cell autonomous effects of human TUBB4AD249N, we generated iPSC derived medium striatal neurons (MSN) from patients with TUBB4AD249N mutation. MSNs were assessed for survival assays between patient and age-matched controls.

Murine Tubb4aD249N/D249N neurons exhibit reduced survival in vitro and decreased axonal length compared to control neurons (p<0.01). A significant decrease in the number of EB3 comets (p<0.05) were seen indicating altered microtubule dynamics. Further MSNs were successfully derived from control and TUBB4AD249N iPSCs, which demonstrated decreased neuronal survival (p<0.05) and increased apoptosis in TUBB4AD249N neurons. Cell-autonomous effects were also seen in murine OLs with a 50% decrease in the number of mature PLP labeled OLs along with decreased complexity in cells of Tubb4aD249N/D249N origin.  

Initial work suggests a cell-autonomous effect on both neuronal and oligodendrocyte lineages in TUBB4AD249N mutations. Ongoing studies are focused on understanding cellular pathways in H-ABC, in order to determine potential therapeutic approaches.

Authors/Disclosures
Akshata Almad, PhD (Children'S Hospital of Philadelphia)
PRESENTER
No disclosure on file
No disclosure on file
Sunetra Sase, PhD (Children's hospital of Philadelphia) No disclosure on file
No disclosure on file
Divya Sirdeshpande No disclosure on file
Asako Takanohashi, PhD, DVM (Children's Hospital of Philadelphia) Dr. Takanohashi has nothing to disclose.
No disclosure on file
Adeline Vanderver, MD, FAAN (Children'S Hospital of Philadelphia) An immediate family member of Dr. Vanderver has received personal compensation for serving as an employee of Maryland Physician Care. The institution of Dr. Vanderver has received research support from Takeda. The institution of Dr. Vanderver has received research support from Passage Bio. The institution of Dr. Vanderver has received research support from Homology. The institution of Dr. Vanderver has received research support from Eli Lilly. The institution of Dr. Vanderver has received research support from Myrtelle. The institution of Dr. Vanderver has received research support from SynaptixBio. The institution of Dr. Vanderver has received research support from PMD Foundation. The institution of Dr. Vanderver has received research support from Ionis. The institution of Dr. Vanderver has received research support from ISD . The institution of Dr. Vanderver has received research support from Boehringer-Ingelheim. The institution of Dr. Vanderver has received research support from Biogen. The institution of Dr. Vanderver has received research support from Sana. The institution of Dr. Vanderver has received research support from Affinia. The institution of Dr. Vanderver has received research support from BridgeBio. The institution of Dr. Vanderver has received research support from Orchard. The institution of Dr. Vanderver has received research support from Minoryx. The institution of Dr. Vanderver has received research support from Forge Biologics. The institution of Dr. Vanderver has received research support from Vigil. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care.