Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways

Ingram, Melissa; Wozniak, Emily A.L.; Duvick, Lisa A.; Yang, Rendong; Bergmann, Paul; Carson, Robert P.; O’Callaghan, Brennon; Zoghbi, Huda Y.; Henzler, Christine; Orr, Harry T.

doi:10.1016/j.neuron.2016.02.011

Cited by 92 publications

(187 citation statements)

References 63 publications

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“…Homer-3 and also impaired glutamatergic signaling were implicated in the pathophysiology of SCA1 by us and by others (Ingram et al, 2016;Ruegsegger et al, 2016;Serra et al, 2004).…”

Section: Discussionmentioning

confidence: 80%

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

Stucki

Ruegsegger

Steiner

et al. 2016

Free Radical Biology and Medicine

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Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ, Free Radical Biology and Medicine, http://dx.doi.org/10.1016/j.freeradbiomed.2016.07.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Homer-3 and also impaired glutamatergic signaling were implicated in the pathophysiology of SCA1 by us and by others (Ingram et al, 2016;Ruegsegger et al, 2016;Serra et al, 2004).…”

Section: Discussionmentioning

confidence: 80%

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

Stucki

Ruegsegger

Steiner

et al. 2016

Free Radical Biology and Medicine

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“…Published data tables from a previous RNA sequencing analysis of gene expression analysis in ATXN1[82Q] mice (Ingram et al, 2016) and from a microarray analysis of gene expression in Atxn1 154Q/2Q mice (Gatchel et al, 2008) were downloaded from the NCBI Gene Expression Omnibus (accession number GSE75778 and GSE991, respectively). Data tables for ATXN2[Q127] mice and ATXN2-BAC-Q72 mice were generated as described above.…”

Section: Analysis Of Ion Channel Gene Expression From Sca1 and Sca2 Micementioning

confidence: 99%

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in Spinocerebellar ataxia type 1

Chopra

Bushart

Cooper

et al. 2020

Preprint

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Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 corepressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1. Figure 3. Regionally-dysregulated ion channel genes form a functional module critical for Purkinje neuron pacemaking (A) The distribution of regularly firing, irregularly firing, and non-firing cells was recorded for Purkinje neurons in the anterior cerebellum and nodular zone. (B) Representative trace from a tonic firing wild-type and non-firing ATXN1[82Q] Purkinje neuron in the anterior cerebellum at P35. (C) Representative trace from wild-type and ATXN1[82Q] Purkinje neurons in the nodular zone at P35. (D) Quantification of the afterhyperpolarization (AHP) and ISI of wild-type and ATXN1[82Q] Purkinje neurons in the anterior cerebellum at P35. (E) Similar to (D), quantification of the AHP and ISI of wild-type and ATXN1[82Q] Purkinje neurons in the nodular zone at P35. (F) Representative traces of wild-type Purkinje neurons in the anterior cerebellum at P35. Traces are shown at baseline (left), after perfusion of 200 nM iberiotoxin (middle), and after perfusion of 200 nM iberiotoxin + 4 µM mibefradil. (G and H) Summary distribution of regularly firing, irregularly firing, and non-firing Purkinje neurons before and after perfusion of 200 nM iberiotoxin (G) and after 200 nM iberiotoxin + 4 µM mibefradil (H). ** denotes p<0.01; *** denotes p<0.001; ns denotes p>0.05; Chi-square test (A, G, H); two-way repeated measures ANOVA with Holm-Sidak correction for multiple comparisons (D, E). Supplementary Figure 3. Spontaneous Purkinje neuron firing in ATXN1[82Q] mice and wild-type controls Patch clamp electrophysiology in acute cerebellar slices from ATXN1[82Q] mice and wild-type controls was performed at P35. (A) Firing frequency in anterior cerebellum and the nodular zone is shown. (B) Coefficient of variation (CV) of the interspike interval (ISI) is shown for Purkinje neurons in the anterior cerebellum and nodular zone. ns denotes p>0.05; two-tailed Student's t-test.

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“…Much like SCA2, SCA1 is due to a polyQ expansion in the RNA binding protein ATAXIN-1 (ATXN1) (66). One observed result of the SCA1 allele is changed ATXN1 association with transcriptional regulatory complexes (67), leading to vastly different Purkinje neuron mRNA profiles (68). However, the exact targets that drive SCA1 pathogenesis are still being determined.…”

Section: Sfk Inhibition Rescues Purkinje Neuron Firing Across Scamentioning

confidence: 99%

BIOLOGICAL SCIENCES: Neuroscience, cell biology MTSS1/Src family kinase Dysregulation Underlies Multiple Inherited Ataxias

Brown

Meera

Altindag

et al. 2018

Preprint

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(153/250 words)The genetically heterogeneous Spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-Metastasis (MTSS1) is a novel ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively.Treatment of each SCA model with a clinically-approved Src inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression. was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/338046 doi: bioRxiv preprint first posted online Jun. 4, 2018; MTSS1/SFK Ataxia 3 of 29 Significance Statement (122/120)The Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system function, and may contribute to neurodegeneration. Spinocerebellar ataxias (SCAs) are neurodegenerative diseases where Purkinje neurons fire irregularly and degenerate leading to motor problems. We show that the SFK suppressor Missing-in-Metastasis (MTSS1) is a novel ataxia gene that links multiple SCAs. MTSS1 loss results in increased SFK activity, degenerating Purkinje neurons with low basal firing rates, and cell death. Surprisingly, mouse models for three different SCAs show elevated SFK activity, with SCA1 and SCA2 models displaying dramatically reduced MTSS1 protein levels. Treatment of each SCA model with SFK inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common link among disparate neurodegenerative diseases.

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Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways

Cited by 92 publications

References 63 publications

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in Spinocerebellar ataxia type 1

BIOLOGICAL SCIENCES: Neuroscience, cell biology MTSS1/Src family kinase Dysregulation Underlies Multiple Inherited Ataxias

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