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

Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring he...

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Main Authors:	Sunetra Sase, Akshata A Almad, C Alexander Boecker, Pedro Guedes-Dias, Jian J Li, Asako Takanohashi, Akshilkumar Patel, Tara McCaffrey, Heta Patel, Divya Sirdeshpande, Julian Curiel, Judy Shih-Hwa Liu, Quasar Padiath, Erika LF Holzbaur, Steven S Scherer, Adeline Vanderver
Format:	Article
Language:	English
Published:	eLife Sciences Publications Ltd 2020-05-01
Series:	eLife
Subjects:	microtubule hypomyelination neurodegeneration leukodystrophy TUBB4A
Online Access:	https://elifesciences.org/articles/52986

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spelling	doaj-d63c220dcb804fd689ffcb48f6975f302021-05-05T21:08:56ZengeLife Sciences Publications LtdeLife2050-084X2020-05-01910.7554/eLife.52986TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse modelSunetra Sase0Akshata A Almad1https://orcid.org/0000-0001-6603-2564C Alexander Boecker2Pedro Guedes-Dias3Jian J Li4Asako Takanohashi5Akshilkumar Patel6Tara McCaffrey7Heta Patel8Divya Sirdeshpande9Julian Curiel10Judy Shih-Hwa Liu11Quasar Padiath12Erika LF Holzbaur13https://orcid.org/0000-0001-5389-4114Steven S Scherer14Adeline Vanderver15https://orcid.org/0000-0002-6290-6751Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United StatesDepartment of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United StatesDepartment of Physiology, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Physiology, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Neurology, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United StatesDepartment of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United StatesDepartment of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United StatesDepartment of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United StatesDepartment of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United StatesDepartment of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United StatesDepartment of Neurology, Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, United StatesDepartment of Human Genetics and Neurobiology, University of Pittsburgh, Pittsburgh, United StatesDepartment of Physiology, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Neurology, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Neurology, The Children's Hospital of Philadelphia, Philadelphia, United States; Department of Neurology, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesMutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4aD249N/+) and the homozygous (Tubb4aD249N/D249N) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4aD249N/D249N mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4aD249N/D249N mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4aD249N/D249N mice. Thus Tubb4aD249N/D249N mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits.https://elifesciences.org/articles/52986microtubulehypomyelinationneurodegenerationleukodystrophyTUBB4A
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Sunetra Sase Akshata A Almad C Alexander Boecker Pedro Guedes-Dias Jian J Li Asako Takanohashi Akshilkumar Patel Tara McCaffrey Heta Patel Divya Sirdeshpande Julian Curiel Judy Shih-Hwa Liu Quasar Padiath Erika LF Holzbaur Steven S Scherer Adeline Vanderver
spellingShingle	Sunetra Sase Akshata A Almad C Alexander Boecker Pedro Guedes-Dias Jian J Li Asako Takanohashi Akshilkumar Patel Tara McCaffrey Heta Patel Divya Sirdeshpande Julian Curiel Judy Shih-Hwa Liu Quasar Padiath Erika LF Holzbaur Steven S Scherer Adeline Vanderver TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model eLife microtubule hypomyelination neurodegeneration leukodystrophy TUBB4A
author_facet	Sunetra Sase Akshata A Almad C Alexander Boecker Pedro Guedes-Dias Jian J Li Asako Takanohashi Akshilkumar Patel Tara McCaffrey Heta Patel Divya Sirdeshpande Julian Curiel Judy Shih-Hwa Liu Quasar Padiath Erika LF Holzbaur Steven S Scherer Adeline Vanderver
author_sort	Sunetra Sase
title	TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model
title_short	TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model
title_full	TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model
title_fullStr	TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model
title_full_unstemmed	TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model
title_sort	tubb4a mutations result in both glial and neuronal degeneration in an h-abc leukodystrophy mouse model
publisher	eLife Sciences Publications Ltd
series	eLife
issn	2050-084X
publishDate	2020-05-01
description	Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4aD249N/+) and the homozygous (Tubb4aD249N/D249N) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4aD249N/D249N mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4aD249N/D249N mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4aD249N/D249N mice. Thus Tubb4aD249N/D249N mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits.
topic	microtubule hypomyelination neurodegeneration leukodystrophy TUBB4A
url	https://elifesciences.org/articles/52986
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TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model

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