A Novel Mutation in Isoform 3 of the Plasma Membrane Ca2+ Pump Impairs Cellular Ca2+ Homeostasis in a Patient with Cerebellar Ataxia and Laminin Subunit 1α Mutations

Calì, Tito; Lopreiato, Raffaele; Shimony, Joshua S.; Vineyard, Marisa; Frizzarin, Martina; Zanni, Ginevra; Zanotti, Giuseppe; Brini, Marisa; Shinawi, Marwan; Carafoli, Ernesto

doi:10.1074/jbc.m115.656496

Cited by 43 publications

(38 citation statements)

References 32 publications

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“…Mutations in several genes with known functions related to calcium homeostasis cause monogenetic forms of ataxia, including those encoding the P type voltage-gated Ca 2+ channel (Zhuchenko et al, 1997), mGluR1 (Guergueltcheva et al, 2012), the type 1 IP 3 R (van de Leemput et al, 2007), the type 3 Ca 2+ ATPase (Zanni et al, 2012; Calì et al, 2015), and possibly TRPC3 (Fogel et al, 2015). Moreover, cerebellar PNs abundantly express many genes involved in calcium homeostasis and a large fraction of these genes are transcriptionally dysregulated in various SCAs (Serra et al, 2004; Schorge et al, 2010; Bettencourt et al, 2014; Ingram et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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

Meera

Pulst

Otis

2017

eLife

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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.DOI: http://dx.doi.org/10.7554/eLife.26377.001

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Section: Discussionmentioning

confidence: 99%

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

Meera

Pulst

Otis

2017

eLife

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“…Loss of a single copy of the gene encoding the plasma membrane calcium pump PMCA also results in ataxia in mice (Empson et al 2010), and rare mutations in this gene have been found in human ataxia patients (Zanni et al 2012;Cali et al 2015). Taken together, such findings strongly suggest that elevated calcium levels, one of the possible outcomes of increased activity in the mGluR signalling cascade, can compromise the health of PNs and lead to ataxia.…”

Section: Evidence Suggesting That Increased Mglur Signalling Plays a mentioning

confidence: 95%

“…; Cali et al . ). Taken together, such findings strongly suggest that elevated calcium levels, one of the possible outcomes of increased activity in the mGluR signalling cascade, can compromise the health of PNs and lead to ataxia.…”

Section: Introductionmentioning

confidence: 97%

Cellular and circuit mechanisms underlying spinocerebellar ataxias

Meera

Pulst

Otis

2016

The Journal of Physiology

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Degenerative ataxias are a common form of neurodegenerative disease that affect about 20 individuals per 100,000. The autosomal dominant spinocerebellar ataxias (SCAs) are caused by a variety of protein coding mutations (single nucleotide changes, deletions and expansions) in single genes. Affected genes encode plasma membrane and intracellular ion channels, membrane receptors, protein kinases, protein phosphatases and proteins of unknown function. Although SCA-linked genes are quite diverse they share two key features: first, they are highly, although not exclusively, expressed in cerebellar Purkinje neurons (PNs), and second, when mutated they lead ultimately to the degeneration of PNs. In this review we summarize ataxia-related changes in PN neurophysiology that have been observed in various mouse knockout lines and in transgenic models of human SCA. We also highlight emerging evidence that altered metabotropic glutamate receptor signalling and disrupted calcium homeostasis in PNs form a common, early pathophysiological mechanism in SCAs. Together these findings indicate that aberrant calcium signalling and profound changes in PN neurophysiology precede PN cell loss and are likely to lead to cerebellar circuit dysfunction that explains behavioural signs of ataxia characteristic of the disease.

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“…The cytoplasmic domains contain an actuator domain A, a phosphorylation domain P and a nucleotide binding domain N. The loop between TM4 and TM5 contains the phosphorylation and ATP binding sites. There are two calcium ion binding sites (Baig et al 2011, Cali et al 2015. Deletion mutations of ATP2B3 were reported together with ATP1A1 (Beuschlein et al 2013) at p.L425_ V426del and p.V426_V427del, which are located in TM4 (Fig.…”

Section: Atp2b3mentioning

confidence: 99%

Genetics of primary hyperaldosteronism

Dutta

Söderkvist

Gimm

2016

Endocrine-Related Cancer

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Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.

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A Novel Mutation in Isoform 3 of the Plasma Membrane Ca2+ Pump Impairs Cellular Ca2+ Homeostasis in a Patient with Cerebellar Ataxia and Laminin Subunit 1α Mutations

Cited by 43 publications

References 32 publications

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

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

Cellular and circuit mechanisms underlying spinocerebellar ataxias

Genetics of primary hyperaldosteronism

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