Role of DJ-1 in Parkinson's Disease

Lev, Nirit; Roncevich, Dusan; Ickowicz, Debby; Melamed, Eldad; Offen, Daniel

doi:10.1385/jmn:29:3:215

Cited by 94 publications

(76 citation statements)

References 77 publications

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“…The abundance of DJ-1 (also called park7), a regulator of the PI3K/Akt pathway, was increased in DM muscles. This protein protects cells from toxic stress, is implicated in mitochondria and oxidative stress-related survival pathways (Lev et al, 2006), and is a novel regulator of the PI3K/ Akt pathway (Kim et al, 2005). The abundance of PTEN, the most important negative regulator of the PI3K/Akt pathway, was found to be downregulated in DM muscles compared to control ones.…”

Section: Discussionmentioning

confidence: 99%

Myostatin inactivation induces a similar muscle molecular signature in double-muscled cattle as in mice

Chelh

Picard

Hocquette

et al. 2011

Animal

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Myostatin (MSTN), a member of the TGF-b superfamily, is a negative regulator of skeletal muscle mass. We have previously shown that the cell survival/apoptosis pathway is a downstream target of MSTN loss-of-function in mice through the regulation of the expression or abundance of many survival and apoptotic factors. In this study, we used western-blot and quantitative PCR (qPCR) analyses to validate these novel downstream targets of MSTN in double-muscled (DM) cattle v. their controls including 260-day-old foetuses and adult cows from the INRA95 strain. MSTN loss-of-function in DM foetuses and DM cows resulted in a glycolytic shift of the muscles (e.g. upregulation of H-MyBP, PGM1 and SNTA1 and downregulation of H-FABP), activation of cell survival pathway through regulation of some components of the PI3K/Akt pathway (e.g. upregulation of DJ-1 and Gsk-3bser9/ Gsk-3btotal ratio and downregulation of PTEN) and upregulation of cell survival factors translationally controlled tumour protein (14-3-3E, Pink1). We also found a lower abundance of pro-apoptotic transcripts and/or proteins (Caspase-3, caspase-8, caspase-9, BID, ID2 and Daxx) and a higher expression of anti-apoptotic transcripts (Traf2 and Bcl2l2) in DM muscles. All together, these results are in favour of activation of the cell survival pathway and loss of apoptosis pathway within the muscles of DM animals. Alteration of both pathways may increase myonuclear or satellite cell survival, which is crucial for protein synthesis. This could contribute to muscle hypertrophy in DM foetuses and DM cows.Keywords: myostatin, cattle, muscle hypertrophy, apoptosis, cell survival ImplicationsMuscle hypertrophy has been extensively studied in meatproducing animals. In double-muscled (DM) cattle, a loss-offunction mutation in the myostatin gene (MSTN ) is responsible for muscle hypertrophy. In order to get a thorough knowledge of the molecular mechanisms of MSTN action, we have examined the molecular phenotype of DM muscle based on our previous data in MSTN-null mice. The data bring new elements to the understanding of the DM muscle phenotype and of the regulation of muscle mass in farm animals.

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Section: Discussionmentioning

confidence: 99%

Myostatin inactivation induces a similar muscle molecular signature in double-muscled cattle as in mice

Chelh

Picard

Hocquette

et al. 2011

Animal

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“…We endogenously tagged HSP31 with the 9myc epitope using a PCR-based integration (12). The pYM20 plasmid was used as a template, and primers were used to obtain PCR product with HSP31 genomic flanking followed by transformation into W303 and W303 ␣Syn-CFP ϩ ␣Syn-YFP strains.…”

Section: Hsp31-9myc Taggingmentioning

confidence: 99%

Hsp31 Is a Stress Response Chaperone That Intervenes in the Protein Misfolding Process

Tsai

Aslam

Drendel

et al. 2015

Journal of Biological Chemistry

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Background: Hsp31 is a multifunctional cellular stress response protein.Results: Hsp31 is a stress-inducible chaperone that has substoichiometric activity on a wide spectrum of substrates, including prions and the non-physiological client, ␣-synuclein. Conclusion: Hsp31 protects cells from ␣-synuclein-mediated toxicity via chaperone activity and independently from enzymatic activity and autophagy. Significance: This is the first characterization of the early acting and wide ranging chaperone activity of Hsp31.

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“…DJ-1 is a multifunctional redox-sensitive protein serving as a molecular chaperone [228], a transport regulator [229,230], and protecting cells against OS [231,232], thus leading to suppression of apoptosis [233]. DJ-1 downregulation enhances cell death by OS, ER stress, and proteasome inhibition [234], while the localization of DJ-1 to mitochondria is associated with protective actions against some mitochondrial poisons [235].…”

Section: The Role Of α-Synuclein Mutationsmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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Role of DJ-1 in Parkinson's Disease

Cited by 94 publications

References 77 publications

Myostatin inactivation induces a similar muscle molecular signature in double-muscled cattle as in mice

Myostatin inactivation induces a similar muscle molecular signature in double-muscled cattle as in mice

Hsp31 Is a Stress Response Chaperone That Intervenes in the Protein Misfolding Process

The role of α-synuclein in neurodegeneration — An update

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