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Front Neurol,
2021]
Neuronal calcium dyshomeostasis has been associated to Parkinson's disease (PD) development based on epidemiological studies on users of calcium channel antagonists and clinical trials are currently conducted exploring the hypothesis of increased calcium influx into neuronal cytosol as basic premise. We reported in 2018 an opposite hypothesis based on the demonstration that alpha-synuclein aggregates stimulate the endoplasmic reticulum (ER) calcium pump SERCA and demonstrated in cell models the existence of an alpha-synuclein-aggregate dependent neuronal state wherein cytosolic calcium is decreased due to an increased pumping of calcium into the ER. Inhibiting the SERCA pump protected both neurons and an alpha-synuclein transgenic C. elegans model. This models two cellular states that could contribute to development of PD. First the prolonged state with reduced cytosolic calcium that could deregulate multiple signaling pathways. Second the disease ER state with increased calcium concentration. We will discuss our hypothesis in the light of recent papers. First, a mechanistic study describing how variation in the Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) may explain GWAS studies identifying the ITPKB gene as a protective factor toward PD. Here it was demonstrated that how increased ITPKB activity reduces influx of ER calcium to mitochondria via contact between IP3-receptors and the mitochondrial calcium uniporter complex in ER-mitochondria contact, known as mitochondria-associated membranes (MAMs). Secondly, it was demonstrated that astrocytes derived from PD patients contain alpha-synuclein accumulations. A recent study has demonstrated how human astrocytes derived from a few PD patients carrying the LRRK2-2019S mutation express more alpha-synuclein than control astrocytes, release more calcium from ER upon ryanodine receptor (RyR) stimulation, show changes in ER calcium channels and exhibit a decreased maximal and spare respiration indicating altered mitochondrial function in PD astrocytes. Here, we summarize the previous findings focusing the effect of alpha-synuclein to SERCA, RyR, IP3R, MCU subunits and other MAM-related channels. We also consider how the SOCE-related events could contribute to the development of PD.
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Neurosci Lett,
2017]
Proteinopathies constitute a diverse group of devastating neurodegenerative disorders, characterized by aberrant aggregation of specific proteins within neurons and in the brain parenchyma. Parkinson's disease (PD) is among the most common proteinopathies, caused by the accumulation of different species of -synuclein and the formation of protein inclusions known as Lewy bodies. Although several mutations in the -synuclein gene have been linked to PD, the mechanisms mediating the aggregation and toxicity of -synuclein are not fully understood. Here, we review recent evidence that highlight an intricate interplay between -synuclein and ionostasis, focusing on the PMR1 pump, a Golgi resident Ca(2+)/Mn(2+) P-type ATPase, which plays a pivotal role in regulating the intracellular levels of calcium and manganese ions.
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Ageing Res Rev,
2014]
Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the -synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The -synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD.
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Genes Dev,
1999]
A wide variety of extracellular stimuli induce signal transduction through receptors coupled to heterotrimeric G proteins, which consist of alpha, beta, and gamma subunits (Gilman 1987). The G alpha subunit has guanine nucleotide binding and GTP hydrolysis activities. Based on function and amino acid sequence homology, the Galpha, G alph i/o, G alpha q, and G alpha 12 (Simon et al. 1991; Hepler and Gilman 1992). As exemplified by the responsiveness of our five senses to environmental stimuli, signaling mediated by trimeric G proteins is often extremely rapid and transient. A key step in achieving such a raid response is the ability of the G alpha subunit to switch between it GDP- and GTP-bound forms. The nucleotide binding state of G alpha is regulated at both the GDP dissociation and GTP hydrolysis steps. Stimulation of receptors by agonists leads to a conformational change in the receptors which can function as a guanine nucleotide exchange factor to stimulate a rapid dissociation of GDP from the inactive G alpha. The nucleotide-free G alpha is then available to bind GTP, leading to the dissociation of G alpha from the G beta gamma heterodimer. Both the G alpha and G beat gamma subunits can interact with and regulate downstream effectors that include adenylyl cyclase, phospholipase C, and ion channels (Gilman 1987; Birnbaumer 1992).
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Mech Ageing Dev,
2001]
Transgenic Drosophila melanogaster and Caenorhabditis elegans strains have been engineered to express human proteins associated with neurodegenerative diseases. These model systems include transgenic animals expressing beta-amyloid peptide (Alzheimer's disease), polyglutamine repeat proteins (Huntington's disease, Spinocerebellar ataxia), and alpha-synuclein (Parkinson's disease). In most of these invertebrate models, some aspects of the human diseases are reproduced, Although expression of all these proteins in transgenic mice has been instructive, the invertebrate models offer experimental advantages (e.g. forward genetic screens) that can potentially address some of the outstanding questions regarding the cellular processes underlying these diseases. This review considers what has been learned from these invertebrate models, and speculates what further insight may be gained from them.
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Mov Disord,
2013]
Impairment of autophagy-lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson's disease (PD). ALP alterations are observed in sporadic PD brains and in toxic and genetic rodent models of PD-related neurodegeneration. In addition, PD-linked mutations and post-translational modifications of -synuclein impair its own lysosomal-mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD-related genes, such as leucine-rich repeat kinase-2 (LRRK2), parkin, and phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal-related genes, such as glucocerebrosidase (GBA) and lysosomal type 5 P-type ATPase (ATP13A2), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, -synuclein accumulation, and neurotoxicity. First, PD-related GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to -synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum-Golgi to lysosomes, leading to neurodegeneration. Second, PD-related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to -synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease-modifying therapeutic strategies aimed at restoring lysosomal levels and function.
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WormBook,
2006]
Heterotrimeric G proteins, composed of alpha , beta , and gamma subunits, are able to transduce signals from membrane receptors to a wide variety of intracellular effectors. In this role, G proteins effectively function as dimers since the signal is communicated either by the G alpha subunit or the stable G betagamma complex. When inactive, G alpha -GDP associates with G betagamma and the cytoplasmic portion of the receptor. Ligand activation of the receptor stimulates an exchange of GTP for GDP resulting in the active signaling molecules G alpha -GTP and free G betagamma , either of which can interact with effectors. Hydrolysis of GTP restores G alpha -GDP, which then reassociates with G betagamma and receptor to terminate signaling. The rate of G protein activation can be enhanced by the guanine-nucleotide exchange factor, RIC-8 , while the rate of GTP hydrolysis can be enhanced by RGS proteins such as EGL-10 and EAT-16 . Evidence for a receptor-independent G-protein-signaling pathway has been demonstrated in C. elegans early embryogenesis. In this pathway, the G alpha subunits GOA-1 and GPA-16 are apparently activated by the non-transmembrane proteins GPR-1 , GPR-2 , and RIC-8 , and negatively regulated by RGS-7 . The C. elegans genome encodes 21 G alpha , 2 G beta and 2 G gamma subunits. The alpha subunits include one ortholog of each mammalian G alpha family: GSA-1 (Gs), GOA-1 (Gi/o), EGL-30 (Gq) and GPA-12 (G12). The remaining C. elegans alpha subunits ( GPA-1 , GPA-2 , GPA-3 , GPA-4 , GPA-5 , GPA-6 , GPA-7 , GPA-8 , GPA-9 , GPA-10 , GPA-11 , GPA-13 , GPA-14 , GPA-15 , GPA-16 , GPA-17 and ODR-3 ) are most similar to the Gi/o family, but do not share sufficient homology to allow classification. The conserved G alpha subunits, with the exception of GPA-12 , are expressed broadly while 14 of the new G alpha genes are expressed in subsets of chemosensory neurons. Consistent with their expression patterns, the conserved C. elegans alpha subunits, GSA-1 , GOA-1 and EGL-30 are involved in diverse and fundamental aspects of development and behavior. GOA-1 acts redundantly with GPA-16 in positioning of the mitotic spindle in early embryos. EGL-30 and GSA-1 are required for viability starting from the first larval stage. In addition to their roles in development and behaviors such as egg laying and locomotion, the EGL-30 , GSA-1 and GOA-1 pathways interact in a network to regulate acetylcholine release by the ventral cord motor neurons. EGL-30 provides the core signals for vesicle release, GOA-1 negatively regulates the EGL-30 pathway, and GSA-1 modulates this pathway, perhaps by providing positional cues. Constitutively activated GPA-12 affects pharyngeal pumping. The G alpha subunits unique to C. elegans are primarily involved in chemosensation. The G beta subunit, GPB-1 , as well as the G gamma subunit, GPC-2 , appear to function along with the alpha subunits in the classic G protein heterotrimer. The remaining G beta subunit, GPB-2 , is thought to regulate the function of certain RGS proteins, while the remaining G gamma subunit, GPC-1 , has a restricted role in chemosensation. The functional difference for most G protein pathways in C. elegans, therefore, resides in the alpha subunit. Many cells in C. elegans express multiple G alpha subunits, and multiple G protein pathways are known to function in specific cell types. For example, Go, Gq and Gs-mediated signaling occurs in the ventral cord motor neurons. Similarly, certain amphid neurons use multiple G protein pathways to both positively and negatively regulate chemosensation. C. elegans thus provides a powerful model for the study of interactions between and regulation of G protein signaling.
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Genome Biol,
2007]
SUMMARY: The integrins are a superfamily of cell adhesion receptors that bind to extracellular matrix ligands, cell-surface ligands, and soluble ligands. They are transmembrane alphabeta heterodimers and at least 18 alpha and eight beta subunits are known in humans, generating 24 heterodimers. Members of this family have been found in mammals, chicken and zebrafish, as well as lower eukaryotes, including sponges, the nematode Caenorhabditis elegans (two alpha and one beta subunits, generating two integrins) and the fruitfly Drosophila melanogaster (five alpha and one beta, generating five integrins). The alpha and beta subunits have distinct domain structures, with extracellular domains from each subunit contributing to the ligand-binding site of the heterodimer. The sequence arginine-glycine-aspartic acid (RGD) was identified as a general integrin-binding motif, but individual integrins are also specific for particular protein ligands. Immunologically important integrin ligands are the intercellular adhesion molecules (ICAMs), immunoglobulin superfamily members present on inflamed endothelium and antigen-presenting cells. On ligand binding, integrins transduce signals into the cell interior; they can also receive intracellular signals that regulate their ligand-binding affinity. Here we provide a brief overview that concentrates mostly on the organization, structure and function of mammalian integrins, which have been more extensively studied than integrins in other organisms.
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Front Genet,
2017]
Parkinson's disease (PD) is a neurodegenerative disorder with symptoms that progressively worsen with age. Pathologically, PD is characterized by the aggregation of -synuclein in cells of the substantia nigra in the brain and loss of dopaminergic neurons. This pathology is associated with impaired movement and reduced cognitive function. The etiology of PD can be attributed to a combination of environmental and genetic factors. A popular animal model, the nematode roundworm Caenorhabditis elegans, has been frequently used to study the role of genetic and environmental factors in the molecular pathology and behavioral phenotypes associated with PD. The current review summarizes cellular markers and behavioral phenotypes in transgenic and toxin-induced PD models of C. elegans.
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Acta Biochimica Polonica,
2005]
Carbohydrates are known as sources of immunological cross-reactivity of allergenic significance. In celery and in cypress pollen, the major allergens Api g 5 and Cup a 1 are recognised by antisera raised against anti-horseradish peroxidase and by patients'''' IgE which apparently bind carbohydrate epitopes; mass spectrometric analysis of the tryptic peptides and of their N-glycans showed the presence of oligosaccharides carrying both xylose and core alpha 1,3-fucose residues. Core alpha 1,3-fucose residues are also a feature of invertebrates: genetic and biochemical studies on the fruitfly Drosophila melanogaster, the parasitic trematode Schistosoma mansoni and the nematode worm Caenorhabditis elegans indicate that these organisms possess core alpha 1,3-fucosyltransferases. Various experiments have shown that fucosyltransferases from both fly and worm are responsible in vivo and in vitro for the synthesis of N-glycans which cross-react with anti-horseradish peroxidase; thus, we can consider these enzymes as useful tools in generating standard compounds for testing cross-reactive carbohydrate epitopes of