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Institute: Centre of Biosciences SAS (Institute of Molecular Physiology and Genetics SAS)

Mitochondria-endoplasmic reticulum functional interplay in Wolfram Syndrome: emerging role for heart and brain protection
Funkčné prepojenie mitochondrií a endoplazmatického retikula u Wolframovho syndrómu: predpokladaný význam pre ochranu mozgu a srdca
Program: FP7
Project leader: RNDr. Cagalinec Michal PhD.
Annotation:Wolfram syndrome (WS)is a recessive neurological disorder caused by mutation of the Wfs1 gene. The Wfs1 protein is highly expressed in the brain and heart and is embedded in the endoplasmic reticulum (ER) where it modulates Ca2+ levels and ER stress. Additionally, the main symptoms of the WSare consistent with the ones characteristic for mitochondrial diseases. In fact, our preliminary results showed already that silencing of Wfs1 in mouse neurons decreased the mitochondrial fusion frequency and caused mitochondrial fragmentation, demonstrating strong impact of Wfs1 to mitochondrial function in neurons. Although the high expression of Wfs1 in the heart and cardiac symptoms in WS identified recently emphasize the functional importance of Wfs1 in the heart, the most common causes of morbidity in WS are the neurological manifestations. How is it possible that mutations of Wfs1 causing significant perturbations in the brain functions are not so prominent in the heart? One explanation of this tissue specificity is that a mechanism compensating for loss of Wfs1 protein function is present in the heart but not in neurons.
Duration: 1.3.2015 - 31.12.2018

Characterization of novel interaction partners of the N-type (Cav2.2) calcium channel
Charakterizácia nových interakčných partnerov N-typu (Cav2.2) vápnikového kanála
Program: Bilateral - other
Project leader: doc. RNDr. Lacinová Ľubica DrSc.
Annotation:In neurons calcium acts as a second messenger mediating numerous physiological responses including synaptic plasticity, secretion of neurotransmitters, activities of various enzymes, gene expression, cellular differentiation, as well as axonal outgrowth. Precise spatiotemporal regulation of free intracellular [Ca2+]i is vital for the integrity and function of a neuronal system. Well-defined pathways for calcium influx from an extracellular space represent individual members of voltage-gated calcium channels (VGCCs). Spatial diversity of calcium signaling is accomplished by highly specific expression of individual channel types in parts of the neuronal cell body, axon, and/or dendrites. N-type or Cav2.2 calcium channels are expressed solely in neurons. These channels are predominantly located at synaptic nerve terminals and calcium influx through Cav2.2 initiates neurotransmitter secretion ensuring transmission of excitatory stimuli to postsynaptic membranes (Wheeler et al. 1994). These are the only VGCCs capable of generating a large but temporally precise calcium influx (Weber et al. 2010). Integration of VGCCs in complex network structures of protein-interactions is a crucial requirement for precise regulation of channel activity. In the past, we took advantage of the specific properties of the yeast split-ubiquitin system to identify novel interaction partners of the 1 subunit of the Cav2.2 calcium channel. This approach is a completely unbiased strategy to identify novel, so far undescribed calcium channel interacting proteins. In these initial studies we specified a series of so far unknown interaction partners: Tetraspanin-13 (published in Mallmann et al., 2013), RTN1 or reticulon, SLC38A1 a member of the solute carrier family 38, Ptgs or prostaglandin D2 synthase, TMEM 223 an uncharacterized transmembrane protein and GRINA a putative glutamate receptor-associated protein. The major aim of our project is to complete the characterization of each of these individual Cav2.2 interactions with the long-term objective to achieve insights into their physiological context. We will concentrate on the following aspects of the Cav2.2 channel interactome: -Characterization of the nature of the interactions We will verify the interaction by means of co-immunoprecipitation and co-localization studies. Where appropriate we will narrow down the relevant binding structures and analyze the specificity of the interaction for Cav2.2 and possibly other VGCCs. -Regulation of voltage- and time-dependent activity of the Cav2.2 channel itself The main role of Cav2.2 channels is the generation of a large but temporally precise calcium influx into presynaptic neurons. Even minor changes in the channel gating may translate into a significant modulation of synaptic transmission. We will characterize voltage dependence and kinetics of activation and inactivation, cumulative inactivation evoked by high-frequency trains of rectangular depolarizing pulses and/or action-potential-like waveforms in the absence and presence of each putative interacting protein. Further, we will estimate the channel opening probability from a relation between maximal ionic and gating currents. -Modulation of a downstream regulatory pathways We will investigate the modulation of Cav2.2 channels activity by intracellular messengers and/or G-proteins in the absence or presence of each interacting protein.
Duration: 1.1.2016 - 31.12.2017

The link between PDS and mitochondria in epileptogenesis
Vzťah medzi PDS a mitochondriami v procese epileptogenézy
Program: Other
Project leader: RNDr. Cagalinec Michal PhD.
Annotation:PDS are increasingly recognized as epileptogenic factors in acquired forms of epilepsies. Prevention of PDS provides a potential means to decrease the numbers of patients developing epilepsy after brain injuries. It is of crucial importance to understand the pathomechanisms of PDS formation (e.g. common molecular links converging in the aftermaths of hemorrhagic bleeding – both subarachnoidal and intracerebral – or of infection, ischemia,…). Since epilepsy develops only in a certain number of patients, i.e. about 20% after severe brain injury, it is of primary interest to define the factors that predispose to acquisition of an epileptic brain condition. A genetic influence has been noted with respect to this predisposition. The mitochondrial state may represent a critical determinant. Indeed, mitochondrial dysfunction is increasingly understood as a precipitating cause of epilepsy. However, the possibility that formation of PDS plays an essential role therein has not been addressed so far, and thus represents an innovative aspect in targeting epileptogenesis. The vital question is whether supporting mitochondrial function during a critical period after brain injuries can be used to prevent subsequent pathogenesis. Answering this question can be envisaged to provide invaluable insights in viable strategies to counteract acquired forms of epilepsies. Additionally, important information regarding mitochondrial implications in neuronal physiology and pathophysiology can be expected to also arise from our approach.
Duration: 1.1.2016 - 30.6.2018

The total number of projects: 3