Dataset Information

A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2.

ABSTRACT: Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions. At parallel fiber synapses, mGluR1-mediated excitatory postsynaptic currents (EPSCs) and associated calcium transients are increased and prolonged in SCA2 PNs. In SCA2 PNs, enhanced mGluR1 function is prevented by buffering [Ca2+] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca2+]. These findings demonstrate a deleterious positive feedback loop involving elevated intracellular calcium and enhanced mGluR1 function, a mechanism likely to contribute to PN dysfunction and loss in SCA2.

SUBMITTER: Meera P

PROVIDER: S-EPMC5444899 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2.

Meera Pratap P Pulst Stefan S Otis Thomas T

eLife 20170518

Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of ph ...[more]

PMID: 28518055

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Project description:Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited, neurodegenerative disease caused by an expansion of polyglutamine tracts in the cytosolic protein ataxin-2 (Atx2). Cerebellar Purkinje cells (PCs) are predominantly affected in SCA2. The cause of PC degeneration in SCA2 is unknown. Here we demonstrate that mutant Atx2-58Q, but not wild-type (WT) Atx2-22Q, specifically associates with the cytosolic C-terminal region of type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1), an intracellular calcium (Ca(2+)) release channel. Association with Atx2-58Q increased the sensitivity of InsP(3)R1 to activation by InsP(3) in planar lipid bilayer reconstitution experiments. To validate physiological significance of these findings, we performed a series of experiments with an SCA2-58Q transgenic mouse model that expresses human full-length Atx2-58Q protein under the control of a PC-specific promoter. In Ca(2+) imaging experiments, we demonstrated that stimulation with 3,5-dihydroxyphenylglycine (DHPG) resulted in higher Ca(2+) responses in 58Q PC cultures than in WT PC cultures. DHPG-induced Ca(2+) responses in 58Q PC cultures were blocked by the addition of ryanodine, an inhibitor of the ryanodine receptor (RyanR). We further demonstrated that application of glutamate induced more pronounced cell death in 58Q PC cultures than in WT PC cultures. Glutamate-induced cell death of 58Q PC cultures was attenuated by dantrolene, a clinically relevant RyanR inhibitor and Ca(2+) stabilizer. In whole animal experiments, we demonstrated that long-term feeding of SCA1-58Q mice with dantrolene alleviated age-dependent motor deficits (quantified in beam-walk and rotarod assays) and reduced PC loss observed in untreated SCA2-58Q mice by 12 months of age (quantified by stereology). Results of our studies indicate that disturbed neuronal Ca(2+) signaling may play an important role in SCA2 pathology and also suggest that the RyanR constitutes a potential therapeutic target for treatment of SCA2 patients.

Project description:Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly undaerstood. Emerging research suggests that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells. Ca2+ signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of Ca2+ channels, Ca2+-dependent kinases and phosphatases, and Ca2+-binding proteins to tightly maintain Ca2+ homeostasis and regulate physiological Ca2+-dependent processes. Abnormal Ca2+ levels can activate toxic cascades leading to characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells via inhibitory signals; thus, Purkinje cell dysfunction or degeneration would partially or completely impair the cerebellar output in SCAs. In the absence of the inhibitory signal emanating from Purkinje cells, DCN will become more excitable, thereby affecting the motor areas receiving DCN input and resulting in uncoordinated movements. An outstanding advantage in studying the pathogenesis of SCAs is represented by the availability of a large number of animal models which mimic the phenotype observed in humans. By mainly focusing on mouse models displaying mutations or deletions in genes which encode for Ca2+ signaling-related proteins, in this review we will discuss the several pathogenic mechanisms related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction.

Dataset Information

A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2.

Publications

A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2.

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