Altered synaptic and firing properties of cerebellar Purkinje cells in a mouse model of ARSACS

Ady, Visou; Toscano-Márquez, Brenda; Nath, Moushumi; Chang, Philip K.-Y.; Hui, Jeanette; Cook, Anna A.; Charron, François; Larivière, Roxanne; Brais, Bernard; McKinney, R. Anne; Watt, Alanna J.

doi:10.1113/jp275902

Cited by 36 publications

(57 citation statements)

References 51 publications

(92 reference statements)

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“…Interestingly, Purkinje cell damage in the brain of the HbSS-BERK mice has been previously observed (6). Purkinje cells are the principal output neurons of the cerebellar cortical microcircuit, and thus play a fundamental role in coordinating cerebellar function by integrating massive excitatory synaptic input, as well as firing high-frequency and highly regular action potentials in the absence of synaptic drive (8). Purkinje cell malfunction has been observed in mouse models of several forms of ataxia, which exhibit alterations in gait (9,10).…”

Section: Introductionmentioning

confidence: 96%

Spatiotemporal Alterations in Gait in Humanized Transgenic Sickle Mice

et al. 2020

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Sickle cell disease (SCD) is a hemoglobinopathy affecting multiple organs and featuring acute and chronic pain. Purkinje cell damage and hyperalgesia have been demonstrated in transgenic sickle mice. Purkinje cells are associated with movement and neural function which may influence pain. We hypothesized that Purkinje cell damage and/or chronic pain burden provoke compensatory gait changes in sickle mice. We found that Purkinje cells undergoe increased apoptosis as shown by caspase-3 activation. Using an automated gait measurement system, MouseWalker, we characterized spatiotemporal gait characteristics of humanized transgenic BERK sickle mice in comparison to control mice. Sickle mice showed alteration in stance instability and dynamic gait parameters (walking speed, stance duration, swing duration and specific swing indices). Differences in stance instability may reflect motor dysfunction due to damaged Purkinje cells. Alterations in diagonal and all stance indices indicative of hesitation during walking may originate from motor dysfunction and/or arise from fear and/or anticipation of movement-evoked pain. We also demonstrate that stance duration, diagonal swing indices and all stance indices correlate with both mechanical and deep tissue hyperalgesia, while stance instability correlates with only deep tissue hyperalgesia. Therefore, objective analysis of gait in SCD may provide insights into neurological impairment and pain states.

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Section: Introductionmentioning

confidence: 96%

Spatiotemporal Alterations in Gait in Humanized Transgenic Sickle Mice

et al. 2020

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“…The exact role of this large, 520-kDa cytoplasmic protein remains unknown, though it has been proposed to have roles in mitochondrial function ( 21 ), protein chaperoning ( 22 ), and the ubiquitin-proteasome system ( 23 ). Further studies have shown that Sacsin knockout results in increased reactive oxygen species production ( 24 ) and alterations in synaptic input and intrinsic firing in cerebellar Purkinje cells ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

A Chromosomal Deletion and New Frameshift Mutation Cause ARSACS in an African-American

et al. 2018

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Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare, progressive, neurodegenerative disease characterized by ataxia, spasticity and polyneuropathy. First described in the French-Canadian population of Quebec in 1978, ARSACS has since been identified in multiple patients worldwide. In this clinical case report, we describe the evaluation of an 11-years-old African-American male who presented to neuromuscular clinic for assessment of a gait abnormality. He had a history of gross motor delay since early childhood, frequent falls and a below average IQ. Chromosomal microarray revealed a 1.422 megabase loss in the 13q12.12 region, which includes the SACS gene. Next Generation Sequencing then showed a novel, predicted to be pathogenic missense mutation (c.11824dup) of this gene. His clinical presentation and neurological imaging further confirmed the diagnosis of ARSACS. To our knowledge, this is the first reported case of this disease in the African-American population of the United States. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide.

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“…PCs from the Sacs À/À mouse model have axonal swellings, characteristic of axonal degeneration. Recent studies have revealed abnormal synaptic input and intrinsic firing in cerebellar PCs, as well as in their synaptic output in the deep cerebellar nuclei in a mouse model of ARSACS [29]. These changes in firing have been observed in anterior lobules that later exhibit PCs death showing that synaptic and intrinsic alterations are related to PCs and likely to contribute to disease manifestation in ARSACS.…”

Section: Disease Modelling Of Arsacsmentioning

confidence: 97%

Short Review: Investigating ARSACS: models for understanding cerebellar degeneration

Castro

Machuca

Jiménez

et al. 2019

Neuropathology Appl Neurobio

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Autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) is an early‐onset neurodegenerative disease that includes progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss‐of‐function mutation in the SACS gene, which encodes for SACSIN. Although animal models are still necessary to investigate the role of SACSIN in the pathology of this disease, more reliable human cellular models need to be generated to better understand the cerebellar pathophysiology of ARSACS. The discovery of human induced pluripotent stem cells (hiPSC) has permitted the derivation of patient‐specific cells. These cells have an unlimited self‐renewing capacity and the ability to differentiate into different neural cell types, allowing studies of disease mechanism, drug discovery and cell replacement therapies. In this study, we discuss how the hiPSC‐derived cerebellar organoid culture offers novel strategies for targeting the pathogenic mutations related to ARSACS. We also highlight the advantages and challenges of this 3D cellular model, as well as the questions that still remain unanswered.

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Altered synaptic and firing properties of cerebellar Purkinje cells in a mouse model of ARSACS

Cited by 36 publications

References 51 publications

Spatiotemporal Alterations in Gait in Humanized Transgenic Sickle Mice

Spatiotemporal Alterations in Gait in Humanized Transgenic Sickle Mice

A Chromosomal Deletion and New Frameshift Mutation Cause ARSACS in an African-American

Short Review: Investigating ARSACS: models for understanding cerebellar degeneration

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