Disorders of Neuronal Migration/Organization Convey the Highest Risk of Neonatal Onset Epilepsy Compared to Other Congenital Brain Malformations

Abstract The microtubule cytoskeleton supports diverse cellular morphogenesis and migration processes during brain development. Mutations in tubulin genes are associated with severe human brain malformations known as ‘tubulinopathies’; however, it is not understood how molecular-level changes in microtubule subunits lead to brain malformations. In this study, we demonstrate that missense mutations affecting arginine at position 402 (R402) of TUBA1A α-tubulin selectively impair dynein motor activity and severely and dominantly disrupt cortical neuronal migration. TUBA1A is the most commonly affected tubulin gene in tubulinopathy patients, and mutations altering R402 account for 30% of all reported TUBA1A mutations. We show for the first time that ectopic expression of TUBA1A-R402C and TUBA1A-R402H patient alleles is sufficient to dominantly disrupt cortical neuronal migration in the developing mouse brain, strongly supporting a causal role in the pathology of brain malformation. To isolate the precise molecular impact of R402 mutations, we generated analogous R402C and R402H mutations in budding yeast α-tubulin, which exhibit a simplified microtubule cytoskeleton. We find that R402 mutant tubulins assemble into microtubules that support normal kinesin motor activity but fail to support the activity of dynein motors. Importantly, the level of dynein impairment scales with the expression level of the mutant in the cell, suggesting a ‘poisoning’ mechanism in which R402 mutant α-tubulin acts dominantly by populating microtubules with defective binding sites for dynein. Based on our results, we propose a new model for the molecular pathology of tubulinopathies that may also extend to other tubulin-related neuropathies.

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Human Brain Malformations and Their Lessons for Neuronal Migration

Annual Review of Neuroscience ◽

10.1146/annurev.neuro.24.1.1041 ◽

2001 ◽

Vol 24 (1) ◽

pp. 1041-1070 ◽

Cited By ~ 159

Author(s):

M Elizabeth Ross ◽

Christopher A Walsh

Keyword(s):

Human Brain ◽

Neuronal Migration ◽

Brain Malformations

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LIS1 and DCX: Implications for Brain Development and Human Disease in Relation to Microtubules

Scientifica ◽

10.1155/2013/393975 ◽

2013 ◽

Vol 2013 ◽

pp. 1-17 ◽

Cited By ~ 19

Author(s):

Orly Reiner

Keyword(s):

Brain Development ◽

Neuronal Migration ◽

Place Of Birth ◽

Microtubule Associated Proteins ◽

Final Destination ◽

Brain Malformations ◽

Wide Range ◽

Associated Functions ◽

Associated Proteins ◽

Neuronal Polarization

Proper lamination of the cerebral cortex requires the orchestrated motility of neurons from their place of birth to their final destination. Improper neuronal migration may result in a wide range of diseases, including brain malformations, such as lissencephaly, mental retardation, schizophrenia, and autism. Ours and other studies have implicated that microtubules and microtubule-associated proteins play an important role in the regulation of neuronal polarization and neuronal migration. Here, we will review normal processes of brain development and neuronal migration, describe neuronal migration diseases, and will focus on the microtubule-associated functions of LIS1 and DCX, which participate in the regulation of neuronal migration and are involved in the human developmental brain disease, lissencephaly.

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Tubulin isotype specificity in neuronal migration: Tuba8 can’t fill in for Tuba1a

The Journal of Cell Biology ◽

10.1083/jcb.201705172 ◽

2017 ◽

Vol 216 (8) ◽

pp. 2247-2249 ◽

Cited By ~ 1

Author(s):

Takeshi Kawauchi

Keyword(s):

Mouse Brain ◽

Neuronal Migration ◽

Adult Mouse ◽

Brain Morphology ◽

Microtubule Organization ◽

Adult Mouse Brain ◽

Tubulin Isotypes ◽

Cell Biol ◽

Brain Malformations ◽

Tubulin Isotype

Several tubulin isotypes, including Tuba1a, are associated with brain malformations. In this issue, Belvindrah et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201607074) show that Tuba1a and Tuba8 differentially regulate microtubule organization in neurons, and they provide insights into the mechanisms by which Tuba1a mutations disrupt adult mouse brain morphology.

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