The ataxia-linked E1081Q mutation affects the sub-plasma membrane Ca-microdomains by tuning PMCA3 activity.

Calcium concentration must be finely tuned in all eukaryotic cells to ensure the correct performance of its signalling function. Neuronal activity is exquisitely dependent on the control of Ca homeostasis: its alterations ultimately play a pivotal role in the origin and progression of many neurodegenerative processes. A complex toolkit of Ca pumps and exchangers maintains the fluctuation of cytosolic Ca concentration within the appropriate threshold.

Remdesivir: From Ebola to COVID-19.

Human coronaviruses (HCoV) were discovered in the 1960s and were originally thought to cause only mild upper respiratory tract diseases in immunocompetent hosts. This view changed since the beginning of this century, with the 2002 SARS (severe acute respiratory syndrome) epidemic and the 2012 MERS (Middle East respiratory syndrome) outbreak, two zoonotic infections that resulted in mortality rates of approximately 10% and 35%, respectively. Despite the importance of these pathogens, no approved antiviral drugs for the treatment of human coronavirus infections became available.

History of the COVID-19 pandemic: Origin, explosion, worldwide spreading.

The SARS-CoV-2 virus of the COVID-19 pandemic, that is presently devastating the entire world, had been active well before January of this year, when its pathogenic potential exploded full force in Wuhan. It had caused the onset of small disease outbreaks in China, and probably elsewhere as well, which failed to reach epidemic potential. The distant general origin of its zoonosis can be traced back to the ecosystem changes that have decreased biodiversity, greatly facilitating the contacts between humans and the animal reservoirs that carry pathogens, including SARS-CoV-2.

Biodiversity loss and COVID-19 pandemic: The role of bats in the origin and the spreading of the disease.

The loss of biodiversity in the ecosystems has created the general conditions that have favored and, in fact, made possible, the insurgence of the COVID-19 pandemic. A lot of factors have contributed to it: deforestation, changes in forest habitats, poorly regulated agricultural surfaces, mismanaged urban growth. They have altered the composition of wildlife communities, greatly increased the contacts of humans with wildlife, and altered niches that harbor pathogens, increasing their chances to come in contact with humans.

COVID19: an announced pandemic.

A severe upper respiratory tract syndrome caused by the new coronavirus has now spread to the entire world as a highly contagious pandemic. The large scale explosion of the disease is conventionally traced back to January of this year in the Chinese province of Hubei, the wet markets of the principal city of Wuhan being assumed to have been the specific causative locus of the sudden explosion of the infection. A number of findings that are now coming to light show that this interpretation of the origin and history of the pandemic is overly simplified.

BCG vaccination policy and preventive chloroquine usage: do they have an impact on COVID-19 pandemic?

Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome caused by Coronavirus 2 (SARS-CoV-2). In the light of its rapid global spreading, on 11 March 2020, the World Health Organization has declared it a pandemic. Interestingly, the global spreading of the disease is not uniform, but has so far left some countries relatively less affected.

Is hydroxychloroquine beneficial for COVID-19 patients?

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019. As similar cases rapidly emerged around the world, the World Health Organization (WHO) declared a public health emergency of international concern on January 30, 2020 and pronounced the rapidly spreading coronavirus outbreak as a pandemic on March 11, 2020. The virus has reached almost all countries of the globe.

A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia.

The fine regulation of intracellular calcium is fundamental for all eukaryotic cells. In neurons, Ca oscillations govern the synaptic development, the release of neurotransmitters and the expression of several genes. Alterations of Ca homeostasis were found to play a pivotal role in neurodegenerative progression.

The PMCA pumps in genetically determined neuronal pathologies.

Ca signals regulate most aspects of animal cell life. They are of particular importance to the nervous system, in which they regulate specific functions, from neuronal development to synaptic plasticity. The homeostasis of cell Ca must thus be very precisely regulated: in all cells Ca pumps transport it from the cytosol to the extracellular medium (the Plasma Membrane Ca ATPases, hereafter referred to as PMCA pumps) or to the lumen of intracellular organelles (the Sarco/Endoplasmatic Reticulum Ca ATPase and the Secretory Pathway Ca ATPase, hereafter referred to as SERCA and SPCA pumps, respectively).

A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: Biochemical characterization of the pump defect.

The neuron-restricted isoform 3 of the plasma membrane Ca ATPase plays a major role in the regulation of Ca homeostasis in the brain, where the precise control of Ca signaling is a necessity. Several function-affecting genetic mutations in the PMCA3 pump associated to X-linked congenital cerebellar ataxias have indeed been described. Interestingly, the presence of co-occurring mutations in additional genes suggest their synergistic action in generating the neurological phenotype as digenic modulators of the role of PMCA3 in the pathologies.

Regulation of Cell Calcium and Role of Plasma Membrane Calcium ATPases.

The plasma membrane Ca ATPase (PMCA pump) is a member of the superfamily of P-type pumps. It has 10 transmembrane helices and 2 cytosolic loops, one of which contains the catalytic center. Its most distinctive feature is a C-terminal tail that contains most of the regulatory sites including that for calmodulin.

The ataxia related G1107D mutation of the plasma membrane Ca ATPase isoform 3 affects its interplay with calmodulin and the autoinhibition process.

The plasma membrane Ca ATPases (PMCA pumps) have a long, cytosolic C-terminal regulatory region where a calmodulin-binding domain (CaM-BD) is located. Under basal conditions (low Ca), the C-terminal tail of the pump interacts with autoinhibitory sites proximal to the active center of the enzyme. In activating conditions (i.

The plasma membrane calcium pumps: focus on the role in (neuro)pathology.

The plasma membrane Ca ATPase (PMCA pump) is a member of the superfamily of P-type pumps. It is organized in the plasma membrane with ten transmembrane helices and two main cytosolic loops, one of which contains the catalytic center. It also contains a long C-terminal tail that houses the binding site for calmodulin, the main regulator of the activity of the pump.

Why Calcium? How Calcium Became the Best Communicator.

Calcium carries messages to virtually all important functions of cells. Although it was already active in unicellular organisms, its role became universally important after the transition to multicellular life. In this Minireview, we explore how calcium ended up in this privileged position.

Spontaneous shaker rat mutant - a new model for X-linked tremor/ataxia.

The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation.

Calcium Handling by Endoplasmic Reticulum and Mitochondria in a Cell Model of Huntington's Disease.

Huntington disease (HD) is caused by the CAG (Q) expansion in exon 1 of the IT15 gene encoding a polyglutamine (poly-Q) stretch of the Huntingtin protein (Htt). In the wild type protein, the repeats specify a stretch of up 34 Q in the N-terminal portion of Htt. In the pathological protein (mHtt) the poly-Q tract is longer.

The Plasma Membrane Ca(2+) ATPase: Purification by Calmodulin Affinity Chromatography, and Reconstitution of the Purified Protein.

Plasma membrane Ca(2+) ATPases (PMCA pumps) are key regulators of cytosolic Ca(2+) in eukaryotes. They extrude Ca(2+) from the cytosol, using the energy of ATP hydrolysis and operate as Ca(2+)-H(+) exchangers. They are activated by the Ca(2+)-binding protein calmodulin, by acidic phospholipids and by other mechanisms, among them kinase-mediated phosphorylation.