Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy.

Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. In the last two decades, numerous gene defects underlying different forms of epilepsy have been identified with most of these genes encoding ion channel proteins. Despite these developments, the etiology of majority of non-familial epilepsies has no known associated genetic mutations and cannot be explained by defects in identified ion channels alone.

Role of synucleins in traumatic brain injury — an experimental in vitro and in vivo study in mice.

Synucleins are small prone to aggregate proteins associated with several neurodegenerative diseases (NDDs), however their role in traumatic brain injury (TBI) is an emerging area of investigation. Using in vitro scratch injury model and in vivo mouse weight-drop model we have found that the injury causes alterations in the expression and localization of synucleins near the damaged area. Before injury, α-synuclein is diffused in the cytoplasm of neurons and γ-synuclein is both in the cytoplasm and nucleus of oligodendrocytes.

New α- and γ-synuclein immunopathological lesions in human brain.

Introduction: Several neurodegenerative diseases are classified as proteopathies as they are associated with the aggregation of misfolded proteins. Synucleinopathies are a group of neurodegenerative disorders associated with abnormal deposition of synucleins. α-Synucleinopathies include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.

Cell-specific post-transcriptional regulation of γ-synuclein gene by micro-RNAs.

γ-Synuclein is a member of the synucleins family of small proteins, which consists of three members:α, β- and γ-synuclein. γ-Synuclein is abnormally expressed in a high percentage of advanced and metastatic tumors, but not in normal or benign tissues. Furthermore, γ-synuclein expression is strongly correlated with disease progression, and can stimulate proliferation, induce invasion and metastasis of cancer cells.

γ-Synuclein: seeding of α-synuclein aggregation and transmission between cells.

Protein misfolding and aggregation is a ubiquitous phenomenon associated with a wide range of diseases. The synuclein family comprises three small naturally unfolded proteins implicated in neurodegenerative diseases and some forms of cancer. α-Synuclein is a soluble protein that forms toxic inclusions associated with Parkinson's disease and several other synucleinopathies.

Expression of caveolin in trabecular meshwork cells and its possible implication in pathogenesis of primary open angle glaucoma.

Purpose: Primary open-angle glaucoma (POAG), which is the most common form of glaucoma, has been associated with a heterogeneous genetic component. A genome-wide association study has identified a common sequence variant at 7q31 (rs4236601 [A]) near the caveolin genes in patients with POAG. Caveolins are a family of integral membrane proteins which participate in many cellular processes, including vesicular transport, cholesterol homeostasis, signal transduction, cell adhesion and migration.

Matrix metalloproteinase 9 expression: new regulatory elements.

Retinal ganglion cells apoptosis is linked to matrix metalloproteinase 9 (MMP-9) controlled changes of extracellular matrix. Abnormal expression of MMP-9 is associated with glaucomatous alterations. Thus, the knowledge of MMP-9 regulation is important for the understanding the pathogenesis of glaucoma.

Effect of gamma-synuclein silencing on apoptotic pathways in retinal ganglion cells.

gamma-Synuclein (Syn G) is highly expressed in retinal ganglion cells and the loss of these cells in glaucoma is associated with significant reduction of the intracellular Syn G level. However, a causative relationship between these two events has not been established. Here we show that the knockdown of Syn G results in a decreased viability of the immortalized retinal ganglion cells (RGC-5).

Gamma-synuclein as a marker of retinal ganglion cells.

Purpose: Previous studies have described gamma-synuclein as a protein highly expressed in retinal ganglion cells (RGCs), and a loss of RGCs correlates with a downregulation of gamma-synuclein gene expression in glaucoma. Here we asked whether gamma-synuclein expression in the retina can be considered a specific marker of RGCs.

Methods: gamma-Synuclein expression was examined with immunohistochemistry in retinal sections from normal and glaucomatous human eyes.

Gamma-synuclein: cell-type-specific promoter activity and binding to transcription factors.

Gamma-synuclein, also referred to as breast-cancer-specific gene 1, is the third member of the neuronal protein family synuclein. Synucleins attracted the attention of many investigators because of their role in human diseases. Gamma-synuclein participates in the pathogenesis of several types of cancer and some neurodegenerative diseases.

gamma-synuclein has a dynamic intracellular localization.

gamma-Synuclein is a member of the synuclein family consisting of three proteins. Within the last several years increasing attention has focused on these proteins because of their role in human diseases. alpha-Synuclein relevance to Parkinson's disease is based on mutations found in familial cases of the disease and its presence in filaments and inclusion bodies in sporadic cases.

Protein aggregation in retinal cells and approaches to cell protection.

1. Retinal dystrophies (RD) comprise a group of clinically and genetically heterogeneous retinal disorders, which typically result in the degeneration of photoreceptors followed by the impairment or loss of vision. Although age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are among the most common forms of RD, currently, there is no effective treatment for either disorder.

Interaction of myocilin with gamma-synuclein affects its secretion and aggregation.

Mutations in the gene encoding human myocilin are associated with some cases of juvenile and early-onset glaucoma. Glaucomatous mutations prevent myocilin from being secreted. The analysis of the defects associated with mutations point to the existence of factor(s) in addition to mutations that might be implicated in the development of glaucoma.

Effect of gamma-synuclein overexpression on matrix metalloproteinases in retinoblastoma Y79 cells.

gamma-Synuclein is a small cytoplasmic protein implicated in neurodegenerative diseases and cancer. However, the mechanism of its involvement in diseases is not clear. We studied the role of gamma-synuclein in the regulation of matrix metalloproteinases in retinoblastoma cell culture.

Synucleins in glaucoma: implication of gamma-synuclein in glaucomatous alterations in the optic nerve.

Synucleins are small proteins associated with neurodegenerative diseases and some forms of cancer. They are studied predominantly in the brain; information about their presence and functions in ocular tissues is scarce. Here we describe the localization of three members of the synuclein family in the optic nerve of donors with different types of glaucoma compared with control samples from donors without ocular diseases.

Gamma synuclein: subcellular localization in neuronal and non-neuronal cells and effect on signal transduction.

Synucleins are small, highly conserved proteins in vertebrates, especially abundant in neurons and typically enriched in presynaptic terminals. alpha-Synuclein protein and a fragment of it, called NAC, have been found in association with pathological lesions of neurodegenerative diseases. Recently, mutations in a alpha-synuclein gene have been reported in families susceptible to an inherited form of Parkinson's diseases.

Synucleins in ocular tissues.

Synucleins are small proteins associated with neurodegenerative diseases and some forms of cancer. Most studies of this group of proteins have been directed to the elucidation of their role in the brain and their connection to the formation of depositions in brain tissues. Here we describe the localization of different types of synucleins in ocular tissues.

Conformational changes in guanylyl cyclase-activating protein 1 (GCAP1) and its tryptophan mutants as a function of calcium concentration.

Guanylyl cyclase-activating proteins (GCAPs are 23-kDa Ca2+-binding proteins belonging to the calmodulin superfamily. Ca2+-free GCAPs are responsible for activation of photoreceptor guanylyl cyclase during light adaptation. In this study, we characterized GCAP1 mutants in which three endogenous nonessential Trp residues were replaced by Phe residues, eliminating intrinsic fluorescence.

Synoretin--A new protein belonging to the synuclein family.

Aoffa-Synuclein, a presynaptic nerve terminal protein, may be an important component of Lewy bodies in Parkinson's disease, dementia with Lewy bodies, and other neurodegenerative diseases. Additionally, recent genetic studies based on linkage analysis and cosegregation of A53T and A30P missense mutations demonstrated that the alpha-synuclein gene may be responsible for the development of at least some cases of familial Parkinson's disease. Despite intense interest in the members of the synuclein family, their function(s) and exact role in the diseases remained unknown.

GCAP1 (Y99C) mutant is constitutively active in autosomal dominant cone dystrophy.

GCAP1 stimulates photoreceptor guanylate cyclase (GC) in bleached vertebrate photoreceptors when [Ca2+]free decreases but is inactivated when cytoplasmic [Ca2+]free increase after dark adaptation. A Y99C mutation in GCAP1 has recently been found to be associated with autosomal dominant cone dystrophy. We show that the GCAP1(Y99C) mutant and native GCAP1 are highly effective in stimulation of photoreceptor GC1.

Changes in biological activity and folding of guanylate cyclase-activating protein 1 as a function of calcium.

Guanylate cyclase-activating protein 1 (GCAP1), a photoreceptor-specific Ca2+-binding protein, activates retinal guanylate cyclase 1 (GC1) during the recovery phase of phototransduction. In contrast to other Ca2+-binding proteins from the calmodulin superfamily, the Ca2+-free form of GCAP1 stimulates the effector enzyme. In this study, we analyzed the Ca2+-dependent changes in GCAP1 structure by limited proteolysis and mutagenesis in order to understand the mechanism of Ca2+-sensitive modulation of GC1 activity.

Localization of guanylate cyclase-activating protein 2 in mammalian retinas.

Guanylate cyclase-activating proteins (GCAP1 and GCAP2) are thought to mediate the intracellular stimulation of guanylate cyclase (GC) by Ca2+, a key event in recovery of the dark state of rod photoreceptors after exposure to light. GCAP1 has been localized to rod and cone outer segments, the sites of phototransduction, and to photoreceptor synaptic terminals and some cone somata. We used in situ hybridization and immunocytochemistry to localize GCAP2 in human, monkey, and bovine retinas.