Loss of β-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans

Emma M. Perkins, Yvonne L. Clarkson, Nancy Sabatier, David M. Longhurst, Christopher P. Millward, Jennifer Jack, Junko Toraiwa, Mitsunori Watanabe, Jeffrey D Rothstein, Alastair R. Lyndon, David J A Wyllie, Mayank B. Dutia, Mandy Jackson

Research output: Contribution to journalArticle

Abstract

Mutations in SPTBN2, the gene encoding β-III spectrin, cause spinocerebellar ataxia type 5 in humans (SCA5), a neurodegenerative disorder resulting in loss of motor coordination. How these mutations give rise to progressive ataxia and what the precise role β-III spectrin plays in normal cerebellar physiology are unknown. We developed a mouse lacking full-length β-III spectrin and found that homozygous mice reproduced features of SCA5 including gait abnormalities, tremor, deteriorating motor coordination, Purkinje cell loss, and cerebellar atrophy (molecular layer thinning). In vivo analysis reveals an age-related reduction in simple spike firing rate in surviving β-III-/- Purkinje cells, whereas in vitro studies show these neurons to have reduced spontaneous firing, smaller sodium currents, and dysregulation of glutamatergic neurotransmission. Our data suggest an early loss of EAAT4-(protein interactor of β-III spectrin) and a subsequent loss of GLAST-mediated uptake may play a role in neuronal pathology. These findings implicate a loss of β-III spectrin function in SCA5 pathogenesis and indicate that there are at least two physiological effects of β-III spectrin loss that underpin a progressive loss of inhibitory cerebellar output, namely an intrinsic Purkinje cell membrane defect due to reduced sodium currents and alterations in glutamate signaling.

Original languageEnglish (US)
Pages (from-to)4857-4867
Number of pages11
JournalJournal of Neuroscience
Volume30
Issue number14
DOIs
StatePublished - Apr 7 2010

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Spinocerebellar Ataxias
Spectrin
Purkinje Cells
Sodium
Mutation
Tremor
Ataxia
Gait
Synaptic Transmission
Neurodegenerative Diseases
Atrophy
Neuropathology
Glutamic Acid
Cell Membrane
Pathology
Neurons
Genes
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

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Loss of β-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. / Perkins, Emma M.; Clarkson, Yvonne L.; Sabatier, Nancy; Longhurst, David M.; Millward, Christopher P.; Jack, Jennifer; Toraiwa, Junko; Watanabe, Mitsunori; Rothstein, Jeffrey D; Lyndon, Alastair R.; Wyllie, David J A; Dutia, Mayank B.; Jackson, Mandy.

In: Journal of Neuroscience, Vol. 30, No. 14, 07.04.2010, p. 4857-4867.

Research output: Contribution to journalArticle

Perkins, EM, Clarkson, YL, Sabatier, N, Longhurst, DM, Millward, CP, Jack, J, Toraiwa, J, Watanabe, M, Rothstein, JD, Lyndon, AR, Wyllie, DJA, Dutia, MB & Jackson, M 2010, 'Loss of β-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans', Journal of Neuroscience, vol. 30, no. 14, pp. 4857-4867. https://doi.org/10.1523/JNEUROSCI.6065-09.2010
Perkins, Emma M. ; Clarkson, Yvonne L. ; Sabatier, Nancy ; Longhurst, David M. ; Millward, Christopher P. ; Jack, Jennifer ; Toraiwa, Junko ; Watanabe, Mitsunori ; Rothstein, Jeffrey D ; Lyndon, Alastair R. ; Wyllie, David J A ; Dutia, Mayank B. ; Jackson, Mandy. / Loss of β-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 14. pp. 4857-4867.
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abstract = "Mutations in SPTBN2, the gene encoding β-III spectrin, cause spinocerebellar ataxia type 5 in humans (SCA5), a neurodegenerative disorder resulting in loss of motor coordination. How these mutations give rise to progressive ataxia and what the precise role β-III spectrin plays in normal cerebellar physiology are unknown. We developed a mouse lacking full-length β-III spectrin and found that homozygous mice reproduced features of SCA5 including gait abnormalities, tremor, deteriorating motor coordination, Purkinje cell loss, and cerebellar atrophy (molecular layer thinning). In vivo analysis reveals an age-related reduction in simple spike firing rate in surviving β-III-/- Purkinje cells, whereas in vitro studies show these neurons to have reduced spontaneous firing, smaller sodium currents, and dysregulation of glutamatergic neurotransmission. Our data suggest an early loss of EAAT4-(protein interactor of β-III spectrin) and a subsequent loss of GLAST-mediated uptake may play a role in neuronal pathology. These findings implicate a loss of β-III spectrin function in SCA5 pathogenesis and indicate that there are at least two physiological effects of β-III spectrin loss that underpin a progressive loss of inhibitory cerebellar output, namely an intrinsic Purkinje cell membrane defect due to reduced sodium currents and alterations in glutamate signaling.",
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AU - Sabatier, Nancy

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AU - Rothstein, Jeffrey D

AU - Lyndon, Alastair R.

AU - Wyllie, David J A

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