Mutant  -III Spectrin Causes mGluR1  Mislocalization and Functional Deficits in a Mouse Model of Spinocerebellar Ataxia Type 5

Armbrust, Karen R; Wang, Xinming; Hathorn, Tyisha; Cramer, Samuel W.; Chen, Gang; Zu, Tao; Kangas, Takashi; Zink, Anastasia N.; Öz, Gülin; Ebner, Timothy J.; Ranum, Laura P.W.

doi:10.1523/jneurosci.0876-14.2014

Cited by 67 publications

(51 citation statements)

References 59 publications

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“…For example, work from Stankewich, Morrow, Ranum, and colleagues demonstrate that βIII spectrin is essential for membrane protein targeting in the nervous system. 35, 36 Similar to our findings in heart, targeted deletion of βIII spectrin in brain results in impaired assembly of the post-synaptic membrane, endomembrane retention of multiple synaptic proteins, as well as ataxia and seizure phenotypes. 36 Moreover, human βIII spectrin gene mutations found in the region where βIII spectrin associates with the dynactin subunit Arp1 37 cause human spinocerebellar ataxia (SCA5) due in to defects in membrane protein (glutamate transporter EAAT4, metabotropic glutamate receptor 1α) targeting.…”

Section: Discussionsupporting

confidence: 84%

“…36 Moreover, human βIII spectrin gene mutations found in the region where βIII spectrin associates with the dynactin subunit Arp1 37 cause human spinocerebellar ataxia (SCA5) due in to defects in membrane protein (glutamate transporter EAAT4, metabotropic glutamate receptor 1α) targeting. 35, 38 Thus, based on βIII spectrin data, as well as our new findings, we hypothesize that βII spectrin is a critical player in membrane protein sorting, versus simply a static membrane structural protein. In fact, the demonstrated links between spectrins and dynactin 37 provide a logical rationale for the cell and molecular phenotypes observed in βII spectrin cKO animals.…”

Section: Discussionsupporting

confidence: 56%

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Dysfunction in the βII Spectrin–Dependent Cytoskeleton Underlies Human Arrhythmia

et al. 2015

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Background The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked with cardiac pathologies including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction in cardiac electrical activity is not well understood, and often overlooked in the cardiac arrhythmia field. Methods and Results Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the post-translational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electrical and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes that include the Na/Ca exchanger, RyR2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. Conclusions Our findings identify βII spectrin as critical for normal myocyte electrical activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 56%

Dysfunction in the βII Spectrin–Dependent Cytoskeleton Underlies Human Arrhythmia

et al. 2015

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“…GluRD2 membrane levels were also lower than in controls [83]. Recently, metabotropic glutamate receptor 1a (mGluR1a) was shown to have reduced localization at dendritic spines and decreased function in a SCA5 mouse model [86]. GluRD2, mGluR1 and PKCc, whose mutations are responsible for SCA14, were all shown to interact in regulating synaptic transmission in PC [87].…”

Section: Glutamate Transmissionmentioning

confidence: 99%

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

2015

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Hereditary cerebellar ataxias (HCAs) are clinically and genetically heterogeneous neurodegenerative disorders, characterised by a cerebellar syndrome and other neurological or non-neurological signs. So far, more than 20 genes have been described in autosomal dominant HCA; in autosomal recessive HCA, even more genes are involved, in often more complex phenotypes. Because of that complexity, the genetic diagnosis of these diseases is often based on the next-generation sequencing techniques. In this review paper, we discuss the major contributions that they have made to the genetic landscape of HCAs. Numerous novel genes have been identified; still more have recently been implicated in HCAs in addition to being responsible for other diseases. The phenotypic spectrum associated with a single gene constantly gains in complexity. Novel types of mutations or transmissions in known genes are regularly being identified. All these factors make genotype-phenotype correlations particularly difficult. Some but not all of this variability can be explained by different pathophysiological consequences (loss of function, gain of function, variable levels of haploinsufficiency). This also raises the question of modifier genes. Finally, we highlight some functional pathways that increasingly appear important in HCAs.

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“…SCA5 is due to mutations of beta-III spectrin, which is a scaffold protein interacting with the mGlu 1 receptor (Armbrust et al, 2014). In SCA5-model mice, the mGlu 1 receptor is decreased in the dendritic spines of PCs, mGlu 1 -mediated Ca 2+ responses are impaired and mGlu 1 -dependent LTP is deficient (Armbrust et al, 2014).…”

Section: Alterations Of the Parallel Fiber-purkinje Cell Synapse In Nmentioning

confidence: 99%

“…In SCA5-model mice, the mGlu 1 receptor is decreased in the dendritic spines of PCs, mGlu 1 -mediated Ca 2+ responses are impaired and mGlu 1 -dependent LTP is deficient (Armbrust et al, 2014). …”

Section: Alterations Of the Parallel Fiber-purkinje Cell Synapse In Nmentioning

confidence: 99%

Modulation, Plasticity and Pathophysiology of the Parallel Fiber-Purkinje Cell Synapse

Hoxha

Tempia

Lippiello

et al. 2016

Front. Synaptic Neurosci.

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The parallel fiber-Purkinje cell (PF-PC) synapse represents the point of maximal signal divergence in the cerebellar cortex with an estimated number of about 60 billion synaptic contacts in the rat and 100,000 billions in humans. At the same time, the Purkinje cell dendritic tree is a site of remarkable convergence of more than 100,000 parallel fiber synapses. Parallel fiber activity generates fast postsynaptic currents via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and slower signals, mediated by mGlu1 receptors, resulting in Purkinje cell depolarization accompanied by sharp calcium elevation within dendritic regions. Long-term depression (LTD) and long-term potentiation (LTP) have been widely described for the PF-PC synapse and have been proposed as mechanisms for motor learning. The mechanisms of induction for LTP and LTD involve different signaling mechanisms within the presynaptic terminal and/or at the postsynaptic site, promoting enduring modification in the neurotransmitter release and change in responsiveness to the neurotransmitter. The PF-PC synapse is finely modulated by several neurotransmitters, including serotonin, noradrenaline and acetylcholine. The ability of these neuromodulators to gate LTP and LTD at the PF-PC synapse could, at least in part, explain their effect on cerebellar-dependent learning and memory paradigms. Overall, these findings have important implications for understanding the cerebellar involvement in a series of pathological conditions, ranging from ataxia to autism. For example, PF-PC synapse dysfunctions have been identified in several murine models of spino-cerebellar ataxia (SCA) types 1, 3, 5 and 27. In some cases, the defect is specific for the AMPA receptor signaling (SCA27), while in others the mGlu1 pathway is affected (SCA1, 3, 5). Interestingly, the PF-PC synapse has been shown to be hyper-functional in a mutant mouse model of autism spectrum disorder, with a selective deletion of Pten in Purkinje cells. However, the full range of methodological approaches, that allowed the discovery of the physiological principles of PF-PC synapse function, has not yet been completely exploited to investigate the pathophysiological mechanisms of diseases involving the cerebellum. We, therefore, propose to extend the spectrum of experimental investigations to tackle this problem.

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Mutant -III Spectrin Causes mGluR1 Mislocalization and Functional Deficits in a Mouse Model of Spinocerebellar Ataxia Type 5

Cited by 67 publications

References 59 publications

Dysfunction in the βII Spectrin–Dependent Cytoskeleton Underlies Human Arrhythmia

Dysfunction in the βII Spectrin–Dependent Cytoskeleton Underlies Human Arrhythmia

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

Modulation, Plasticity and Pathophysiology of the Parallel Fiber-Purkinje Cell Synapse

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