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STIM1 R304W causes muscle degeneration and impaired platelet activation in mice.

ABSTRACT: STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304?W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304?W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304?W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.

SUBMITTER: Gamage TH

PROVIDER: S-EPMC6481308 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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STIM1 R304W causes muscle degeneration and impaired platelet activation in mice.

Gamage Thilini H TH Gunnes Gjermund G Lee Robert Hugh RH Louch William Edward WE Holmgren Asbjørn A Bruton Joseph D JD Lengle Emma E Kolstad Terje R Selnes TRS Revold Tobias T Amundsen Silja Svanstrøm SS Dalen Knut Tomas KT Holme Pål Andre PA Tjønnfjord Geir Erland GE Christensen Geir G Westerblad Håkan H Klungland Arne A Bergmeier Wolfgang W Misceo Doriana D Frengen Eirik E

Cell calcium 20181005

STIM1 and ORAI1 regulate store-operated Ca<sup>2+</sup> entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304 W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304 W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expr ...[more]

PMID: 30390422

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Project description:BackgroundNumerous studies indicate an association between neurodegenerative and metabolic diseases. Although still a matter of debate, growing evidence from epidemiological and animal studies indicate that preexisting diabetes increases the risk to develop Parkinson's disease. However, the mechanisms of such an association are unknown.ObjectivesWe investigated whether diabetes alters striatal dopamine neurotransmission and assessed the vulnerability of nigrostriatal neurons to neurodegeneration.MethodsWe used streptozotocin-treated and genetically diabetic db/db mice. Expression of oxidative stress and nigrostriatal neuronal markers and levels of dopamine and its metabolites were monitored. Dopamine release and uptake were assessed using fast-scan cyclic voltammetry. 6-Hydroxydopamine was unilaterally injected into the striatum using stereotaxic surgery. Motor performance was scored using specific tests.ResultsDiabetes resulted in oxidative stress and decreased levels of dopamine and its metabolites in the striatum. Levels of proteins regulating dopamine release and uptake, including the dopamine transporter, the Girk2 potassium channel, the vesicular monoamine transporter 2, and the presynaptic vesicle protein synaptobrevin-2, were decreased in diabetic mice. Electrically evoked levels of extracellular dopamine in the striatum were enhanced, and altered dopamine uptake was observed. Striatal microinjections of a subthreshold dose of the neurotoxin 6-hydroxydopamine in diabetic mice, insufficient to cause motor alterations in nondiabetic animals, resulted in motor impairment, higher loss of striatal dopaminergic axons, and decreased neuronal cell bodies in the substantia nigra.ConclusionsOur results indicate that diabetes promotes striatal oxidative stress, alters dopamine neurotransmission, and increases vulnerability to neurodegenerative damage leading to motor impairment. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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STIM1 R304W causes muscle degeneration and impaired platelet activation in mice.

Publications

STIM1 R304W causes muscle degeneration and impaired platelet activation in mice.

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