α-Synuclein: Its Biological Function and Role in Neurodegenerative Diseases

Kaplan, Batia; Ratner, Vladimir; Haas, Elisha

doi:10.1385/jmn:20:2:83

Cited by 54 publications

(30 citation statements)

References 82 publications

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“…Such structural changes into the protein may have detrimental effects on protein function. Protein disorder has been demonstrated to play a central role in diseases mediated by protein misfolding and aggregation, for example Alzheimer's and Huntington's diseases and amyloidosis [Schweers et al, 1994;Kaplan et al, 2003;Bates, 2003;Grateau et al, 2005]. Of the missense mutations in HNE, 25% are predicted to cause increase in structural disorder by most of the methods (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Thusberg

Vihinen

2006

Hum. Mutat.

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For the Immunogenetics Special IssueCyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

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Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Thusberg

Vihinen

2006

Hum. Mutat.

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“…21 a-Synuclein inhibits the enzyme tyrosine hydroxylase, thereby downregulating the synthesis of dopamine (DA). 22,23 a-Synuclein is implicated in neurodegenerative disorders 24 such as Parkinson's disease, [25][26][27][28] and high levels of a-synuclein mRNA have been associated with alcoholism in humans 29,30 and alcohol preference in rats. 31 Since anxiety is a common feature in Parkinson's patients, 32 and also in alcoholics, 33,34 a-synuclein may also be important in anxiety.…”

Section: Introductionmentioning

confidence: 99%

Expression of α-synuclein is increased in the hippocampus of rats with high levels of innate anxiety

et al. 2008

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A genomic region neighboring the a-synuclein gene, on rat chromosome 4, has been associated with anxiety-and alcohol-related behaviors in different rat strains. In this study, we have investigated potential molecular and physiological links between a-synuclein and the behavioral differences observed between Lewis (LEW) and Spontaneously Hypertensive (SHR) inbred rats, a genetic model of anxiety. As expected, LEW rats appeared more fearful than SHR rats in three anxiety models: open field, elevated plus maze and light/dark box. Moreover, LEW rats displayed a higher preference for alcohol and consumed higher quantities of alcohol than SHR rats. a-Synuclein mRNA and protein concentrations were higher in the hippocampus, but not the hypothalamus of LEW rats. This result inversely correlated with differences in dopamine turnover in the hippocampus of LEW and SHR rats, supporting the hypothesis that a-synuclein is important in the downregulation of dopamine neurotransmission. A novel single nucleotide polymorphism was identified in the 3 0 -untranslated region (3 0 -UTR) of the asynuclein cDNA between these two rat strains. Plasmid constructs based on the LEW 3 0 -UTR sequence displayed increased expression of a reporter gene in transiently transfected PC12 cells, in accordance with in-vivo findings, suggesting that this nucleotide exchange might participate in the differential expression of a-synuclein between LEW and SHR rats. These results are consistent with a novel role for a-synuclein in modulating rat anxiety-like behaviors, possibly through dopaminergic mechanisms. Since the behavioral and genetic differences between these two strains are the product of independent evolutionary histories, the possibility that polymorphisms in the a-synuclein gene may be associated with vulnerability to anxiety-related disorders in humans requires further investigation.

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“…␣-Synuclein is a protein of as yet unknown function, which is believed to play a role in a wide array of neurodegenerative disorders including Dementia with Lewy bodies, Lewy body variant of Alzheimer disease, and Parkinson disease (1)(2)(3). Collectively, these disorders have been referred to as being synucleinopathies (4,5), with the vast majority of synucleinopathies being sporadic in nature.…”

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confidence: 99%

α-Synuclein Alters Proteasome Function, Protein Synthesis, and Stationary Phase Viability

Chen

Thorpe

Keller

2005

Journal of Biological Chemistry

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␣-Synuclein appears to play a role in mediating neurotoxicity in a number of neurodegenerative disorders, collectively referred to as synucleinopathies. Most of these disorders are associated with aging and a probable impairment of the proteasome-proteolytic pathway, although the relationship between aging, proteasome inhibition, and ␣-synuclein toxicity has not been fully elucidated. Recent studies suggest that yeast may provide a useful system for studying the biology and toxicity of ␣-synuclein in mitotic cells, recapitulating many features observed in the various synucleinopathy disorders. Additional studies indicate that the stationary phase model of aging in yeast provides a useful system for understanding the biochemistry and regulation of aging in post-mitotic cells. In the present study we examined the effect of wild type and mutant ␣-synuclein (A30P) on multiple aspects of proteasome homeostasis, protein synthesis, as well as the ability of cells to survive stationary phase aging. These data demonstrate that ␣-synuclein alters proteasome composition, impairs proteasome-mediated protein degradation, impairs protein synthesis, and impairs the ability of cells to withstand stationary phase aging. Interestingly, ␣-synuclein had little effect on intracellular proteasome content or protein ubiquitination, and did not increase the vulnerability of cells to a variety of stressors. Together, these data suggest that yeast may be useful for understanding the ability of ␣-synuclein to impair proteasome-mediated protein degradation, as well as for understanding the basis for age-related ␣-synuclein cytotoxicity.

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α-Synuclein: Its Biological Function and Role in Neurodegenerative Diseases

Cited by 54 publications

References 82 publications

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Expression of α-synuclein is increased in the hippocampus of rats with high levels of innate anxiety

α-Synuclein Alters Proteasome Function, Protein Synthesis, and Stationary Phase Viability

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