Posterior cerebellar Purkinje cells in an SCA5/SPARCA1 mouse model are especially vulnerable to the synergistic effect of loss of β-III spectrin and GLAST

Emma M. Perkins, Daumante Suminaite, Yvonne L. Clarkson, Sin Kwan Lee, Alastair R. Lyndon, Jeffrey D Rothstein, David J A Wyllie, Kohichi Tanaka, Mandy Jackson

Research output: Contribution to journalArticle

Abstract

Clinical phenotypes of spinocerebellar ataxia type-5 (SCA5) and spectrin-associated autosomal recessive cerebellar ataxia type-1 (SPARCA1) are mirrored in mice lacking β-III spectrin (β-III-/-). One function of β-III spectrin is the stabilization of the Purkinje cell-specific glutamate transporter EAAT4 at the plasma membrane. In β-III-/- mice EAAT4 levels are reduced from an early age. In contrast levels of the predominant cerebellar glutamate transporter GLAST, expressed in Bergmann glia, only fall progressively from 3 months onwards. Here we elucidated the roles of these two glutamate transporters in cerebellar pathogenesis mediated through loss of β-III spectrin function by studying EAAT4 and GLAST knockout mice as well as crosses of both with β-III-/- mice. Our data demonstrate that EAAT4 loss, but not abnormal AMPA receptor composition, in young b- III-/- mice underlies early Purkinje cell hyper-excitability and that subsequent loss of GLAST, superimposed on the earlier deficiency of EAAT4, is responsible for Purkinje cell loss and progression of motor deficits. Yet the loss of GLAST appears to be independent of EAAT4 loss, highlighting that other aspects of Purkinje cell dysfunction underpin the pathogenic loss of GLAST. Finally, our results demonstrate that Purkinje cells in the posterior cerebellum of β-III-/- mice are most susceptible to the combined loss of EAAT4 and GLAST, with degeneration of proximal dendrites, the site of climbing fibre innervation, most pronounced. This highlights the necessity for efficient glutamate clearance from these regions and identifies dysregulation of glutamatergic neurotransmission particularly within the posterior cerebellumas a key mechanism in SCA5 and SPARCA1 pathogenesis.

Original languageEnglish (US)
Pages (from-to)4448-4461
Number of pages14
JournalHuman Molecular Genetics
Volume25
Issue number20
StatePublished - 2016

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Spinocerebellar Ataxias
Spectrin
Purkinje Cells
Amino Acid Transport System X-AG
AMPA Receptors
Dendrites
Knockout Mice
Synaptic Transmission
Neuroglia
Cerebellum
Glutamic Acid
Cell Membrane
Autosomal Recessive Cerebellar Ataxia Type 1
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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Posterior cerebellar Purkinje cells in an SCA5/SPARCA1 mouse model are especially vulnerable to the synergistic effect of loss of β-III spectrin and GLAST. / Perkins, Emma M.; Suminaite, Daumante; Clarkson, Yvonne L.; Lee, Sin Kwan; Lyndon, Alastair R.; Rothstein, Jeffrey D; Wyllie, David J A; Tanaka, Kohichi; Jackson, Mandy.

In: Human Molecular Genetics, Vol. 25, No. 20, 2016, p. 4448-4461.

Research output: Contribution to journalArticle

Perkins, EM, Suminaite, D, Clarkson, YL, Lee, SK, Lyndon, AR, Rothstein, JD, Wyllie, DJA, Tanaka, K & Jackson, M 2016, 'Posterior cerebellar Purkinje cells in an SCA5/SPARCA1 mouse model are especially vulnerable to the synergistic effect of loss of β-III spectrin and GLAST', Human Molecular Genetics, vol. 25, no. 20, pp. 4448-4461.
Perkins, Emma M. ; Suminaite, Daumante ; Clarkson, Yvonne L. ; Lee, Sin Kwan ; Lyndon, Alastair R. ; Rothstein, Jeffrey D ; Wyllie, David J A ; Tanaka, Kohichi ; Jackson, Mandy. / Posterior cerebellar Purkinje cells in an SCA5/SPARCA1 mouse model are especially vulnerable to the synergistic effect of loss of β-III spectrin and GLAST. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 20. pp. 4448-4461.
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abstract = "Clinical phenotypes of spinocerebellar ataxia type-5 (SCA5) and spectrin-associated autosomal recessive cerebellar ataxia type-1 (SPARCA1) are mirrored in mice lacking β-III spectrin (β-III-/-). One function of β-III spectrin is the stabilization of the Purkinje cell-specific glutamate transporter EAAT4 at the plasma membrane. In β-III-/- mice EAAT4 levels are reduced from an early age. In contrast levels of the predominant cerebellar glutamate transporter GLAST, expressed in Bergmann glia, only fall progressively from 3 months onwards. Here we elucidated the roles of these two glutamate transporters in cerebellar pathogenesis mediated through loss of β-III spectrin function by studying EAAT4 and GLAST knockout mice as well as crosses of both with β-III-/- mice. Our data demonstrate that EAAT4 loss, but not abnormal AMPA receptor composition, in young b- III-/- mice underlies early Purkinje cell hyper-excitability and that subsequent loss of GLAST, superimposed on the earlier deficiency of EAAT4, is responsible for Purkinje cell loss and progression of motor deficits. Yet the loss of GLAST appears to be independent of EAAT4 loss, highlighting that other aspects of Purkinje cell dysfunction underpin the pathogenic loss of GLAST. Finally, our results demonstrate that Purkinje cells in the posterior cerebellum of β-III-/- mice are most susceptible to the combined loss of EAAT4 and GLAST, with degeneration of proximal dendrites, the site of climbing fibre innervation, most pronounced. This highlights the necessity for efficient glutamate clearance from these regions and identifies dysregulation of glutamatergic neurotransmission particularly within the posterior cerebellumas a key mechanism in SCA5 and SPARCA1 pathogenesis.",
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AU - Perkins, Emma M.

AU - Suminaite, Daumante

AU - Clarkson, Yvonne L.

AU - Lee, Sin Kwan

AU - Lyndon, Alastair R.

AU - Rothstein, Jeffrey D

AU - Wyllie, David J A

AU - Tanaka, Kohichi

AU - Jackson, Mandy

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N2 - Clinical phenotypes of spinocerebellar ataxia type-5 (SCA5) and spectrin-associated autosomal recessive cerebellar ataxia type-1 (SPARCA1) are mirrored in mice lacking β-III spectrin (β-III-/-). One function of β-III spectrin is the stabilization of the Purkinje cell-specific glutamate transporter EAAT4 at the plasma membrane. In β-III-/- mice EAAT4 levels are reduced from an early age. In contrast levels of the predominant cerebellar glutamate transporter GLAST, expressed in Bergmann glia, only fall progressively from 3 months onwards. Here we elucidated the roles of these two glutamate transporters in cerebellar pathogenesis mediated through loss of β-III spectrin function by studying EAAT4 and GLAST knockout mice as well as crosses of both with β-III-/- mice. Our data demonstrate that EAAT4 loss, but not abnormal AMPA receptor composition, in young b- III-/- mice underlies early Purkinje cell hyper-excitability and that subsequent loss of GLAST, superimposed on the earlier deficiency of EAAT4, is responsible for Purkinje cell loss and progression of motor deficits. Yet the loss of GLAST appears to be independent of EAAT4 loss, highlighting that other aspects of Purkinje cell dysfunction underpin the pathogenic loss of GLAST. Finally, our results demonstrate that Purkinje cells in the posterior cerebellum of β-III-/- mice are most susceptible to the combined loss of EAAT4 and GLAST, with degeneration of proximal dendrites, the site of climbing fibre innervation, most pronounced. This highlights the necessity for efficient glutamate clearance from these regions and identifies dysregulation of glutamatergic neurotransmission particularly within the posterior cerebellumas a key mechanism in SCA5 and SPARCA1 pathogenesis.

AB - Clinical phenotypes of spinocerebellar ataxia type-5 (SCA5) and spectrin-associated autosomal recessive cerebellar ataxia type-1 (SPARCA1) are mirrored in mice lacking β-III spectrin (β-III-/-). One function of β-III spectrin is the stabilization of the Purkinje cell-specific glutamate transporter EAAT4 at the plasma membrane. In β-III-/- mice EAAT4 levels are reduced from an early age. In contrast levels of the predominant cerebellar glutamate transporter GLAST, expressed in Bergmann glia, only fall progressively from 3 months onwards. Here we elucidated the roles of these two glutamate transporters in cerebellar pathogenesis mediated through loss of β-III spectrin function by studying EAAT4 and GLAST knockout mice as well as crosses of both with β-III-/- mice. Our data demonstrate that EAAT4 loss, but not abnormal AMPA receptor composition, in young b- III-/- mice underlies early Purkinje cell hyper-excitability and that subsequent loss of GLAST, superimposed on the earlier deficiency of EAAT4, is responsible for Purkinje cell loss and progression of motor deficits. Yet the loss of GLAST appears to be independent of EAAT4 loss, highlighting that other aspects of Purkinje cell dysfunction underpin the pathogenic loss of GLAST. Finally, our results demonstrate that Purkinje cells in the posterior cerebellum of β-III-/- mice are most susceptible to the combined loss of EAAT4 and GLAST, with degeneration of proximal dendrites, the site of climbing fibre innervation, most pronounced. This highlights the necessity for efficient glutamate clearance from these regions and identifies dysregulation of glutamatergic neurotransmission particularly within the posterior cerebellumas a key mechanism in SCA5 and SPARCA1 pathogenesis.

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