TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model

Sase, Sunetra; Almad, Akshata; Boecker, C. Alexander; Guedes-Dias, Pedro; Li, Jian J.; Takanohashi, Asako; Patel, Akshilkumar; McCaffrey, Tara; Patel, Heta; Sirdeshpande, Divya; Curiel, Julian; Liu, Judy Shih-Hwa; Padiath, Quasar Saleem; Holzbaur, Erika L.F.; Scherer, Steven S.; Vanderver, Adeline

doi:10.7554/elife.52986

Cited by 17 publications

(22 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results showed severe deficits in myelination in Jit mice at P48. These results are consistent with previous reports showing hypomyelination phenotypes due to Tubb4a mutations in rodent models (20,42).…”

Section: A Missense Mutation In Tubb4a Causes Myelination and Cerebel...supporting

confidence: 94%

A dominant tubulin mutation causes cerebellar neurodegeneration in a genetic model of tubulinopathy

Fertuzinhos

Legué

et al. 2022

Sci. Adv.

View full text Add to dashboard Cite

Mutations in tubulins cause distinct neurodevelopmental and degenerative diseases termed “tubulinopathies”; however, little is known about the functional requirements of tubulins or how mutations cause cell-specific pathologies. Here, we identify a mutation in the gene Tubb4a that causes degeneration of cerebellar granule neurons and myelination defects. We show that the neural phenotypes result from a cell type–specific enrichment of a dominant mutant form of Tubb4a relative to the expression other β-tubulin isotypes. Loss of Tubb4a function does not underlie cellular pathology but is compensated by the transcriptional up-regulation of related tubulin genes in a cell type–specific manner. This work establishes that the expression of a primary tubulin mutation in mature neurons is sufficient to promote cell-autonomous cell death, consistent with a causative association of microtubule dysfunction with neurodegenerative diseases. These studies provide evidence that mutations in tubulins cause specific phenotypes based on expression ratios of tubulin isotype genes.

show abstract

Section: A Missense Mutation In Tubb4a Causes Myelination and Cerebel...supporting

confidence: 94%

A dominant tubulin mutation causes cerebellar neurodegeneration in a genetic model of tubulinopathy

Fertuzinhos

Legué

et al. 2022

Sci. Adv.

View full text Add to dashboard Cite

show abstract

“…Resolution of the cell type -specific expression in the mouse brain reveals that TUBB4a is almost exclusively expressed in the oligodendroglial lineage in the cortex, while in humans low expression in astrocytes and neurons was detected (Zhang et al, 2014(Zhang et al, , 2016. Recent development of an accurate mouse model of H-ABC now opens up pre-clinical investigation (Sase et al, 2020). Based on the gain of function hypothesis, a potential therapy would be largely oligodendrocyte focused, directed to reduce mutated tubulin β-4a protein while restoring its wt form.…”

Section: Hypomyelination With Atrophy Of the Basal Ganglia And Cerebellummentioning

confidence: 99%

Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies

Jonquières

Rae

Housley

2021

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Central Nervous System (CNS) homeostasis and function rely on intercellular synchronization of metabolic pathways. Developmental and neurochemical imbalances arising from mutations are frequently associated with devastating and often intractable neurological dysfunction. In the absence of pharmacological treatment options, but with knowledge of the genetic cause underlying the pathophysiology, gene therapy holds promise for disease control. Consideration of leukodystrophies provide a case in point; we review cell type – specific expression pattern of the disease – causing genes and reflect on genetic and cellular treatment approaches including ex vivo hematopoietic stem cell gene therapies and in vivo approaches using adeno-associated virus (AAV) vectors. We link recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future.

show abstract

“…According to the neuropathological phenotype characterized by the loss of putaminal neurons and oligodendrocytes [ 98 , 99 , 201 , 211 , 212 ], D249N mutation has been reported to affect both neuronal and oligodendroglial precursor cells in vitro and in a H-ABC mouse model [ 219 , 220 ].…”

Section: Microtubule Dysfunction and Neurodegenerationmentioning

confidence: 99%

Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases

Sferra

Nicita

Bertini

2020

IJMS

View full text Add to dashboard Cite

Neurons are particularly susceptible to microtubule (MT) defects and deregulation of the MT cytoskeleton is considered to be a common insult during the pathogenesis of neurodegenerative disorders. Evidence that dysfunctions in the MT system have a direct role in neurodegeneration comes from findings that several forms of neurodegenerative diseases are associated with changes in genes encoding tubulins, the structural units of MTs, MT-associated proteins (MAPs), or additional factors such as MT modifying enzymes which modulating tubulin post-translational modifications (PTMs) regulate MT functions and dynamics. Efforts to use MT-targeting therapeutic agents for the treatment of neurodegenerative diseases are underway. Many of these agents have provided several benefits when tested on both in vitro and in vivo neurodegenerative model systems. Currently, the most frequently addressed therapeutic interventions include drugs that modulate MT stability or that target tubulin PTMs, such as tubulin acetylation. The purpose of this review is to provide an update on the relevance of MT dysfunctions to the process of neurodegeneration and briefly discuss advances in the use of MT-targeting drugs for the treatment of neurodegenerative disorders.

show abstract

TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model

Cited by 17 publications

References 48 publications

A dominant tubulin mutation causes cerebellar neurodegeneration in a genetic model of tubulinopathy

A dominant tubulin mutation causes cerebellar neurodegeneration in a genetic model of tubulinopathy

Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies

Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases

Contact Info

Product

Resources

About