Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44

Watson, Lauren M.; Bamber, Elizabeth; Schnekenberg, Ricardo Parolin; Williams, Jonathan M. J.; Bettencourt, Conceição; Jayawant, Sandeep; Lickiss, Jennifer; Fawcett, Katherine A.; Clokie, Samuel; Wallis, Yvonne; Clouston, Penny; Sims, David; Houlden, Henry; Becker, Esther B. E.; Németh, Andrea H.

doi:10.1016/j.ajhg.2017.09.006

Cited by 11 publications

(13 citation statements)

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“…However, it is hypothesized that the context of disease proteins may be important for toxicity, as disease proteins may alter the function of protein interactors, resulting in concomitant loss and gainof-function effects. These concomitant effects are particularly evident in SCA1 and SCA3 (Fogel et al, 2015;Watson et al, 2017). Collectively, these findings paradoxically indicate that both increased and decreased function of disease affected proteins can cause similar deficits to Purkinje cell signaling, detrimentally impacting cerebellar output and movement (Meera et al, 2016).…”

Section: Pgc1α and Sirtuinmentioning

confidence: 99%

“…Glutamate is the most abundant neurotransmitter within the mammalian brain. Under normal conditions, glutamate can trigger transient increases in calcium levels within Purkinje cells via activation of mGluRs and ionotropic, such as AMPA receptors and NMDA receptors (Piochon et al, 2010;Kasumu et al, 2012a;Watson et al, 2017). Historically, Purkinje cells were thought to lack NMDA receptors, relying on other glutamatergic receptors to modulate glutamate signaling (Perkel et al, 1990;Llano et al, 1991).…”

Section: Glutamate Signaling Within the Cerebellummentioning

confidence: 99%

“…Metabotropic glutamate receptor type 1 (mGluR1), encoded by GRM1 gene, is one of the most highly expressed receptor types within the mammalian central nervous system, with particularly high abundance in Purkinje cells (Watson et al, 2017). Neuronal excitability is modulated by mGluRs, which yield slow excitatory post-synaptic currents, and excitatory amino acid transporters (EAATs), which transport glutamate (Power and Empson, 2014).…”

Section: Glutamate Signaling Within the Cerebellummentioning

confidence: 99%

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Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias

2020

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The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative diseases that share convergent disease features. A common symptom of these diseases is development of ataxia, involving impaired balance and motor coordination, usually stemming from cerebellar dysfunction and neurodegeneration. For most spinocerebellar ataxias, pathology can be attributed to an underlying gene mutation and the impaired function of the encoded protein through loss or gain-of-function effects. Strikingly, despite vast heterogeneity in the structure and function of disease-causing genes across the SCAs and the cellular processes affected, the downstream effects have considerable overlap, including alterations in cerebellar circuitry. Interestingly, aberrant function and degeneration of Purkinje cells, the major output neuronal population present within the cerebellum, precedes abnormalities in other neuronal populations within many SCAs, suggesting that Purkinje cells have increased vulnerability to cellular perturbations. Factors that are known to contribute to perturbed Purkinje cell function in spinocerebellar ataxias include altered gene expression resulting in altered expression or functionality of proteins and channels that modulate membrane potential, downstream impairments in intracellular calcium homeostasis and changes in glutamatergic input received from synapsing climbing or parallel fibers. This review will explore this enhanced vulnerability and the aberrant cerebellar circuitry linked with it in many forms of SCA. It is critical to understand why Purkinje cells are vulnerable to such insults and what overlapping pathogenic mechanisms are occurring across multiple SCAs, despite different underlying genetic mutations. Enhanced understanding of disease mechanisms will facilitate the development of treatments to prevent or slow progression of the underlying neurodegenerative processes, cerebellar atrophy and ataxic symptoms.

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Section: Pgc1α and Sirtuinmentioning

confidence: 99%

Section: Glutamate Signaling Within the Cerebellummentioning

confidence: 99%

Section: Glutamate Signaling Within the Cerebellummentioning

confidence: 99%

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Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias

2020

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“…Furthermore, mutations in PKCɣ and mGluR1 are known to cause human SCA14 [72,73] and SCA44 [74]. As we have not detected changes in mGluR1 expression pattern (Fig.…”

Section: The W246g Elovl4 Mutation Disrupts Synaptic Plasticity At Exmentioning

confidence: 59%

W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34

Nagaraja

Sherry

Fessler

et al. 2021

Preprint

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Background: Spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders characterized by neuronal degeneration leading to loss of motor coordination. A number of different mutations gives rise to different types of SCA with characteristic ages of onset, symptomatology, and rates of progression. SCA type 34 (SCA34) is an age-related cerebellar neurodegenerative disorder caused by mutations in the fatty acid elongase-4 (ELOVL4). The ELOVL4 is an essential enzyme that mediates biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp., ≥28 carbons) that are critical for the normal function of brain, skin, retina, Meibomian glands, and testes in which ELOVL4 is expressed. Global deletion or homozygous expression of truncated mutant ELOVL4 that lack VLC-SFA and VLC-PUFA biosynthesis cause severe skin disorders, seizures and neonatal mortality in rodents and humans. Methods: To understand role of ELOVL4 and its products in neuronal function and to evaluate the consequences of ELOVL4 mutations in pathogenesis of age-related SCA34, we generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. We performed biochemical, neuroanatomical and behavioral analyses by rotorod to measure motor function. We used electrophysiological recordings from cerebellar slices to determine the impact of the W246G mutation on neuronal function. Results were analyzed using GraphPad Prism Statistical software. Results: Heterozygous and homozygous rats carrying the W246G mutation developed impaired motor deficits by two months of age. To understand the mechanism of these motor deficits, we performed electrophysiological studies using cerebellar slices from rats homozygous for W246G mutant ELOVL4 and found marked reduction of long-term potentiation at parallel fiber synapses and long-term depression at climbing fiber synapses onto Purkinje cells. Neuroanatomical analysis of the cerebellum up 6 months of age showed normal cytoarchitectural organization despite the early-onset motor deficits and defects in synaptic plasticity. Conclusions: Our results point to ELOVL4 and its products being essential for motor function and cerebellar synaptic plasticity. The results further suggest that in SCA34 patients, ataxia arises from primary impairment of synaptic plasticity and cerebellar network desynchronization that precedes cerebellar degeneration and loss of motor coordination with aging.

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“…Rare missense and frame-shift mutations in the GRM1 gene encoding metabotropic glutamate receptor 1 (mGlu1) result in congenital cerebellar ataxia, global developmental delays and moderate to severe intellectual deficit (Davarniya et al, 2015; Guergueltcheva et al, 2012) (Watson et al, 2017). Brain imaging studies of affected individuals also describe progressive involution of the cerebellum and a constitutionally small brain in some subjects (Guergueltcheva et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The G protein-Coupled Metabotropic Glutamate Receptor 1 controls neuronal macroautophagy

Donoso

Speranza

Kalinowska

et al. 2020

Preprint

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Autophagy is an evolutionarily conserved, highly regulated catabolic process critical to neuronal homeostasis, function and survival throughout organismal lifespan. However, the external factors and signals that control autophagy in neurons are still poorly understood. Here we report that the G protein-coupled metabotropic glutamate receptor 1 (mGlu1) contributes to control basal autophagy in the brain. Autophagy is upregulated in the brain of adult mGlu1 knockout mice and genetic deletion or pharmacological inhibition of native mGlu1 receptors enhances autophagy flux in neurons. The evolutionarily conserved adaptor protein FEZ1, identified by a genome-wide screen as mGlu1 receptor interacting partner, was found to participate in the regulation of neuronal autophagy and to be required for repression of autophagy flux by the mGlu1 receptor. Furthermore, FEZ1 appears to enable association of mGlu1 with Ulk1, a core component of the autophagy pathway. Thus, we propose that the mGlu1 receptor contributes to restrain constitutive autophagy in neurons.

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Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44

Cited by 11 publications

References 0 publications

Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias

Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias

W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34

The G protein-Coupled Metabotropic Glutamate Receptor 1 controls neuronal macroautophagy

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