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Alpha Synuclein

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Leonidas Stefanis – One of the best experts on this subject based on the ideXlab platform.

  • How is AlphaSynuclein cleared from the cell?
    Journal of neurochemistry, 2019
    Co-Authors: Leonidas Stefanis, Kostas Vekrellis, Evangelia Emmanouilidou, Marina Pantazopoulou, Deniz Kirik, George K. Tofaris
    Abstract:

    The levels and conformers of AlphaSynuclein are critical in the pathogenesis of Parkinson‘s Disease and related Synucleinopathies. Homeostatic mechanisms in protein degradation and secretion have been identified as regulators of AlphaSynuclein at different stages of its intracellular trafficking and transcellular propagation. Here we review pathways involved in the removal of various forms of AlphaSynuclein from both the intracellular and extracellular environment. Proteasomes and lysosomes are likely to play complementary roles in the removal of intracellular AlphaSynuclein species, in a manner that depends on AlphaSynuclein post-translational modifications. Extracellular AlphaSynuclein is cleared by extracellular proteolytic enzymes, or taken up by neighboring cells, especially microglia and astrocytes, and degraded within lysosomes. Exosomes, on the other hand, represent a vehicle for egress of excess burden of the intracellular protein, potentially contributing to the transfer of AlphaSynuclein between cells. Dysfunction in any one of these clearance mechanisms, or a combination thereof, may be involved in the initiation or progression of Parkinson‘s disease, whereas targeting these pathways may offer an opportunity for therapeutic intervention. (Figure presented.). (Less)

  • Alpha Synuclein and protein degradation systems a reciprocal relationship
    Molecular Neurobiology, 2013
    Co-Authors: Maria Xilouri, Leonidas Stefanis, Oeystein Roed Brekk
    Abstract:

    An increasing wealth of data indicates a close relationship between the presynaptic protein AlphaSynuclein and Parkinson’s disease (PD) pathogenesis. AlphaSynuclein protein levels are considered as a major determinant of its neurotoxic potential, whereas secreted extracellular AlphaSynuclein has emerged as an additional important factor in this regard. However, the manner of AlphaSynuclein degradation in neurons remains contentious. Both the ubiquitin–proteasome system (UPS) and the autophagy–lysosome pathway (ALP)—mainly macroautophagy and chaperone-mediated autophagy—have been suggested to contribute to AlphaSynuclein turnover. Additionally, other proteases such as calpains, neurosin, and metalloproteinases have been also proposed to have a role in intracellular and extracellular AlphaSynuclein processing. Both UPS and ALP activity decline with aging and such decline may play a pivotal role in many neurodegenerative conditions. Alterations in these major proteolytic pathways may result in AlphaSynuclein accumulation due to impaired clearance. Conversely, increased AlphaSynuclein protein burden promotes the generation of aberrant species that may impair further UPS or ALP function, generating thus a bidirectional positive feedback loop leading to neuronal death. In the current review, we summarize the recent findings related to AlphaSynuclein degradation, as well as to AlphaSynuclein-mediated aberrant effects on protein degradation systems. Identifying the factors that regulate AlphaSynuclein association to cellular proteolytic pathways may represent potential targets for therapeutic interventions in PD and related Synucleinopathies.

  • AlphaSynuclein degradation by autophagic pathways: a potential key to Parkinson’s disease pathogenesis.
    Autophagy, 2008
    Co-Authors: Maria Xilouri, Tereza Vogiatzi, Kostas Vekrellis, Leonidas Stefanis
    Abstract:

    The neuronal protein AlphaSynuclein is thought to be central in the pathogenesis of Parkinson‘s disease (PD). Excessive wild type AlphaSynuclein levels can lead to PD in select familial cases and AlphaSynuclein protein accumulation occurs in sporadic PD. Therefore, elucidation of the mechanisms that control AlphaSynuclein levels is critical for PD pathogenesis and potential therapeutics. The subject of AlphaSynuclein degradation has been controversial. Previous work shows that, in an assay with isolated liver lysosomes, purified wild type AlphaSynuclein is degraded by the process of chaperone-mediated autophagy (CMA). Whether this actually occurs in a cellular context has been unclear. In our most recent work, we find that wild type AlphaSynuclein, but not the closely related protein beta-Synuclein, is indeed degraded by CMA in neuronal cells, including primary postnatal ventral midbrain neurons. Macroautophagy, but not the proteasome, also contributes to AlphaSynuclein degradation. Therefore, two separate lysosomal pathways, CMA and macroautophagy, degrade wild type AlphaSynuclein in neuronal cells. It is hypothesized that impairment of either of these two pathways, or of more general lysosomal function, may be an initiating factor in AlphaSynuclein accumulation and sporadic PD pathogenesis.

Vladimir I. Muronetz – One of the best experts on this subject based on the ideXlab platform.

  • Modification by glyceraldehyde-3-phosphate prevents amyloid transformation of AlphaSynuclein.
    Biochimica et biophysica acta. Proteins and proteomics, 2019
    Co-Authors: K.v. Barinova, Marina V. Serebryakova, Elena V. Schmalhausen, Evgeny V. Sheval, Vladimir I. Muronetz
    Abstract:

    Abstract Numerous investigations point to the relation between diabetes and neurodegenerative disorders. AlphaSynuclein is a protein involved in the development of Synucleinopathies including Parkinson‘s disease. In the present work, AlphaSynuclein was for the first time modified by the intermediate product of glycolysis, glyceraldehyde-3-phosphate (GA-3-P). The resulting product was compared with the AlphaSynuclein modified by methylglyoxal (MGO). The efficiency of the modification by the aldehydes was evaluated by decrease in free amino group content. The modification products were detected using fluorescence spectroscopy. The effect of modification by two glycating agents on the amyloid transformation of AlphaSynuclein was investigated. Transmission elecelectron microscopy analysis of the aggregates produced by the native AlphaSynuclein under fibrillation conditions revealed the presence of 355–441-nm fibrils. In the aggregates produced by the modified AlphaSynuclein, short fibrils of 65–230 nm or 85–260 nm were detected in the case of the protein treated with MGO and GA-3-P, respectively. Investigation of the aggregates by the fluorescence assay with Thioflavin T and CD spectroscopy showed that, in contrast to native AlphaSynuclein, AlphaSynuclein treated with GA-3-P does not produce real amyloid structures. Consequently, modification of AlphaSynuclein by GA-3-P, the metabolite whose concentration is determined by the activity of glyceraldehyde-3-phosphate dehydrogenase, prevents its amyloid transformation.

  • Dimerization of Tyr136Cys AlphaSynuclein prevents amyloid transformation of wild type AlphaSynuclein.
    International journal of biological macromolecules, 2016
    Co-Authors: K.v. Barinova, M.l. Kuravsky, Alexander M. Arutyunyan, Marina V. Serebryakova, Elena V. Schmalhausen, Vladimir I. Muronetz
    Abstract:

    Abstract Expression of human AlphaSynuclein in E. coli cells is known to result in a mixture of the wild type AlphaSynuclein and the protein containing Tyr136Cys substitution due to the translational error. The amount of Cys136 AlphaSynuclein (Cys136-AS) may reach approximately 50% of the recombinant protein. The wild-type and Cys136-containing fractions of AlphaSynuclein were separated using thiol-Sepharose, and their properties were investigated. In the absence of reducing agents, Cys136-AS forms dimers due to the disulfide bonding. Both wild-type and Cys136 AlphaSynuclein preparations are prone to aggregate during prolonged incubation under shaking at pH 4 and 37 °C, but only the wild-type AlphaSynuclein produces amyloid aggregates. The aggregates produced by either monomeric or dimeric Cys136-AS do not exhibit amyloid properties according to the test with Thioflavin T. Moreover, an admixture of dimeric Cys136-AS prevents the amyloid transformation of the wild-type AlphaSynuclein. CD spectroscopy analysis revealed an enhanced content of Alpha-helical structures in the aggregates produced by dimeric Cys136-AS. The admixture of Cys136-AS in preparations of human recombinant AlphaSynuclein can be a source of erroneous interpretation of experiments on amyloid transformation of this protein.

Shigenobu Nakamura – One of the best experts on this subject based on the ideXlab platform.

  • Tyrosine 125 of AlphaSynuclein plays a critical role for dimerization following nitrative stress.
    Brain research, 2002
    Co-Authors: Tetsuya Takahashi, Hiroshi Yamashita, Takeshi Nakamura, Yoshito Nagano, Shigenobu Nakamura
    Abstract:

    AlphaSynuclein is a major component of Lewy bodies in Parkinson‘s disease, dementia with Lewy bodies, and glial cytoplasmic inclusions in multiple system atrophy. Increasing evidence suggests that the nitration of tyrosine residues in AlphaSynuclein induced by oxidative injury is involved in the formation of inclusions characteristic to these Synucleinopathies. Exposure of AlphaSynuclein to peroxynitrite induces nitration of tyrosine residues, thereby forming AlphaSynuclein oligomers. However, the contribution of tyrosine residues to either the nitration or the oligomerization is currently unknown. The present study used recombinant wild-type and mutant AlphaSynuclein proteins to investigate the role of each AlphaSynuclein tyrosine residue in the in vitro formation of AlphaSynuclein oligomers under nitrative stress. Confocal microscopic analysis revealed that wild-type AlphaSynuclein protein was able to accumulate and form an inclusion-like structure in the cytoplasm of living cells upon introduction by streptolysin O. Authentic peroxynitrite induced nitration of tyrosine residues in AlphaSynuclein protein, as well as dimerization of AlphaSynuclein. The formation of both SDS- and heat-stable dimers suggests cross-linking between nitrated tyrosine residues. Nonetheless, dimerization of AlphaSynuclein proteins lacking tyrosine 125 was significantly decreased compared with AlphaSynuclein proteins lacking tyrosine residues at positions 39, 133, or 136. Presumably, tyrosine 125 plays a critical role for AlphaSynuclein dimerization under nitrative stress.

  • Activated Fyn phosphorylates AlphaSynuclein at tyrosine residue 125.
    Biochemical and biophysical research communications, 2001
    Co-Authors: Takeshi Nakamura, Tetsuya Takahashi, Hiroshi Yamashita, Shigenobu Nakamura
    Abstract:

    AlphaSynuclein is a presynaptic protein of unknown function that has been implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson‘s and Alzheimer’s diseases. To gain insight into the functions of AlphaSynuclein, we sought protein kinases that phosphorylate AlphaSynuclein in the central nervous system. In contrast to Lyn, PYK2, FAK, MAPK/ERK1, SAPK/JNK, and Cdk5, only Fyn could phosphorylate AlphaSynuclein. In addition, A30P and A53T mutations did not affect the phosphorylation of AlphaSynuclein by Fyn. Mutation analysis revealed that activated Fyn phosphorylates specifically tyrosine residue 125 of AlphaSynuclein. The distribution of AlphaSynuclein and Fyn expression was similar in various parts of the brain and was colocalized in subcellular structures. Since Fyn regulates various signal transduction pathways in the central nervous system and plays an essential role in the neuronal cell differentiation, survival, and plasticity, results of this paper indicate that phosphorylation of AlphaSynuclein might be involved in one of the Fyn-mediated signaling pathways in neuronal cells.

Gültekin Tamgüney – One of the best experts on this subject based on the ideXlab platform.

  • Prion-like propagation of human brain-derived AlphaSynuclein in transgenic mice expressing human wild-type AlphaSynuclein.
    Acta neuropathologica communications, 2015
    Co-Authors: Maria Eugenia Bernis, Julius T. Babila, Sara Breid, Katharina Annick Wüsten, Ullrich Wüllner, Gültekin Tamgüney
    Abstract:

    Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that are characterized by the intracellular accumulation of AlphaSynuclein containing aggregates. Recent increasing evidence suggests that Parkinson’s disease and MSA pathology spread throughout the nervous system in a spatiotemporal fashion, possibly by prion-like propagation of AlphaSynuclein positive aggregates between synaptically connected areas. Concurrently, intracerebral injection of pathological AlphaSynuclein into transgenic mice overexpressing human wild-type AlphaSynuclein, or human AlphaSynuclein with the familial A53T mutation, or into wild-type mice causes spreading of AlphaSynuclein pathology in the CNS. Considering that wild-type mice naturally also express a threonine at codon 53 of AlphaSynuclein, it has remained unclear whether human wild-type AlphaSynuclein alone, in the absence of endogenously expressed mouse AlphaSynuclein, would support a similar propagation of AlphaSynuclein pathology in vivo. Here we show that brain extracts from two patients with MSA and two patients with probable incidental Lewy body disease (iLBD) but not phosphate-buffered saline induce prion-like spreading of pathological AlphaSynuclein after intrastriatal injection into mice expressing human wild-type AlphaSynuclein. Mice were sacrificed at 3, 6, and 9 months post injection and analyzed neuropathologically and biochemically. Mice injected with brain extracts from patients with MSA or probable iLBD both accumulated intraneuronal inclusion bodies, which stained positive for phosphorylated AlphaSynuclein and appeared predominantly within the injected brain hemisphere after 6 months. After 9 months these intraneuronal inclusion bodies had spread to the contralateral hemisphere and more rostral and caudal areas. Biochemical analysis showed that brains of mice injected with brain extracts from patients with MSA and probable iLBD contained hyperphosphorylated AlphaSynuclein that also seeded aggregation of recombinant human wild-type AlphaSynuclein in a Thioflavin T binding assay. Our results indicate that human wild-type AlphaSynuclein supports the prion-like spreading of AlphaSynuclein pathology in the absence of endogenously expressed mouse AlphaSynuclein in vivo.

Maria Xilouri – One of the best experts on this subject based on the ideXlab platform.

  • Alpha Synuclein and protein degradation systems a reciprocal relationship
    Molecular Neurobiology, 2013
    Co-Authors: Maria Xilouri, Leonidas Stefanis, Oeystein Roed Brekk
    Abstract:

    An increasing wealth of data indicates a close relationship between the presynaptic protein AlphaSynuclein and Parkinson’s disease (PD) pathogenesis. AlphaSynuclein protein levels are considered as a major determinant of its neurotoxic potential, whereas secreted extracellular AlphaSynuclein has emerged as an additional important factor in this regard. However, the manner of AlphaSynuclein degradation in neurons remains contentious. Both the ubiquitin–proteasome system (UPS) and the autophagy–lysosome pathway (ALP)—mainly macroautophagy and chaperone-mediated autophagy—have been suggested to contribute to AlphaSynuclein turnover. Additionally, other proteases such as calpains, neurosin, and metalloproteinases have been also proposed to have a role in intracellular and extracellular AlphaSynuclein processing. Both UPS and ALP activity decline with aging and such decline may play a pivotal role in many neurodegenerative conditions. Alterations in these major proteolytic pathways may result in AlphaSynuclein accumulation due to impaired clearance. Conversely, increased AlphaSynuclein protein burden promotes the generation of aberrant species that may impair further UPS or ALP function, generating thus a bidirectional positive feedback loop leading to neuronal death. In the current review, we summarize the recent findings related to AlphaSynuclein degradation, as well as to AlphaSynuclein-mediated aberrant effects on protein degradation systems. Identifying the factors that regulate AlphaSynuclein association to cellular proteolytic pathways may represent potential targets for therapeutic interventions in PD and related Synucleinopathies.

  • AlphaSynuclein degradation by autophagic pathways: a potential key to Parkinson’s disease pathogenesis.
    Autophagy, 2008
    Co-Authors: Maria Xilouri, Tereza Vogiatzi, Kostas Vekrellis, Leonidas Stefanis
    Abstract:

    The neuronal protein AlphaSynuclein is thought to be central in the pathogenesis of Parkinson’s disease (PD). Excessive wild type AlphaSynuclein levels can lead to PD in select familial cases and AlphaSynuclein protein accumulation occurs in sporadic PD. Therefore, elucidation of the mechanisms that control AlphaSynuclein levels is critical for PD pathogenesis and potential therapeutics. The subject of AlphaSynuclein degradation has been controversial. Previous work shows that, in an assay with isolated liver lysosomes, purified wild type AlphaSynuclein is degraded by the process of chaperone-mediated autophagy (CMA). Whether this actually occurs in a cellular context has been unclear. In our most recent work, we find that wild type AlphaSynuclein, but not the closely related protein beta-Synuclein, is indeed degraded by CMA in neuronal cells, including primary postnatal ventral midbrain neurons. Macroautophagy, but not the proteasome, also contributes to AlphaSynuclein degradation. Therefore, two separate lysosomal pathways, CMA and macroautophagy, degrade wild type AlphaSynuclein in neuronal cells. It is hypothesized that impairment of either of these two pathways, or of more general lysosomal function, may be an initiating factor in AlphaSynuclein accumulation and sporadic PD pathogenesis.