Understanding the molecular causes of Parkinson's disease

Wood‐Kaczmar, Alison; Gandhi, Sonia; Wood, Nicholas

doi:10.1016/j.molmed.2006.09.007

Cited by 284 publications

(198 citation statements)

References 87 publications

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“…According to the Swiss-Prot database, DJ-1 may act as a redox-sensitive chaperone and as a sensor for oxidative stress, and it may protect neurons against oxidative stress and cell death. Moreover, DJ-1 is a biomarker in Parkinson's disease (Kubo et al, 2006;Wood-Kaczmar et al, 2006). Although the HTT2800 contained almost no iron, DJ-1 was down-regulated more than in HTT1800, which contains a small amount of iron.…”

Section: Discussionmentioning

confidence: 98%

Proteomics-based safety evaluation of multi-walled carbon nanotubes

Haniu

Matsuda

Takeuchi

et al. 2010

Toxicology and Applied Pharmacology

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Section: Discussionmentioning

confidence: 98%

Proteomics-based safety evaluation of multi-walled carbon nanotubes

Haniu

Matsuda

Takeuchi

et al. 2010

Toxicology and Applied Pharmacology

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“…The identification of several genes linked to familial PD has provided potential insight into the mechanisms of neurodegeneration (16). Important biological themes such as protein aggregation, protein turnover, and mitochondrial dysfunction have been highlighted.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP

Haque

Thomas

D'Souza

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

227

252

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PTEN-induced putative kinase 1 (Pink1) is a recently identified gene linked to a recessive form of familial Parkinson's disease (PD). The kinase contains a mitochondrial localization sequence and is reported to reside, at least in part, in mitochondria. However, neither the manner by which the loss of Pink1 contributes to dopamine neuron loss nor its impact on mitochondrial function and relevance to death is clear. Here, we report that depletion of Pink1 by RNAi increased neuronal toxicity induced by MPP ؉ . Moreover, wild-type Pink1, but not the G309D mutant linked to familial PD or an engineered kinase-dead mutant K219M, protects neurons against MPTP both in vitro and in vivo. Intriguingly, a mutant that contains a deletion of the putative mitochondrial-targeting motif was targeted to the cytoplasm but still provided protection against 1-methyl-4-phenylpyridine (MPP ؉ )/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. In addition, we also show that endogenous Pink1 is localized to cytosolic as well as mitochondrial fractions. Thus, our findings indicate that Pink1 plays a functional role in the survival of neurons and that cytoplasmic targets, in addition to its other actions in the mitochondria, may be important for this protective effect.Parkinson's disease ͉ neurodegeneration ͉ neuroprotection P arkinson's disease (PD) is a movement disorder with progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc). The molecular events responsible for the loss of dopaminergic neurons in PD remain poorly understood. One common feature of PD is the dysfunction of mitochondria, which results in reduced complex I activity in the SNc (1, 2). Experimentally, inhibitors of complex I of the mitochondrial respiratory chain can recapitulate this selective dopaminergic neuronal loss and consequent behavioral deficits (1, 3-5). These observations support the hypothesis that nigral dopamine neurons are highly vulnerable to stress arising from mitochondrial dysfunction.Recently, several genes have been identified that cause PD (6). These genes include ␣-synuclein, parkin, PTEN-induced putative kinase 1 (Pink1), DJ-1, and LRRK2. Although several of the genes have been partially localized to the mitochondria, Pink1 is the only gene with a putative mitochondrial targeting motif. Several studies have shown that the mitochondrial targeting motif at the Nterminal region of Pink1 is sufficient to direct proteins to the mitochondria (7). Pink1 was initially identified as a PTEN-inducible transcript and contains a serine/threonine kinase domain (8). Interestingly, the G309D mutation of the kinase domain leads to a mild decrease in mitochondrial complex I activity, elevation of superoxide radicals, and increased lipid peroxidation (9). Studies with Drosophila lacking Pink1 showed mitochondrial pathology with the similar phenotype as seen in Parkin knockout flies (10, 11). The above observations suggest that mitochondrial dysfunction may be linked to the Pink1 PD phenotype.The mechanisms by which Pi...

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“…The buffer was exchanged to a solution containing 10 mM Tris (pH 7.0), 100 mM NaCl, 5 mM dithiothreitol, 5% glycerol, 1 mM EDTA, and finally the protein was concentrated to 18 mg/ml. For NMR study, 15 N-labeled and 13 C, 15 N-double labeled samples were prepared using M9 minimal medium with 15 15 N resonance assignments were performed by measuring the three-dimensional HNCACB, three-dimensional CBCA(CO)NH (25), and three-dimensional CCH-TOCSY (26) spectra. Interproton distance restraints for structural calculation were obtained from three-dimensional 13 C-edited NOESY-HSQC, three-dimensional 15 N-edited NOESY-HSQC, and two-dimensional NOESY spectra using a 100-ms mixing time.…”

Section: Methodsmentioning

confidence: 99%

“…For instance, the reduced form of Trx1, a mammalian cytosolic isoform, binds to and thereby inhibits the activity of apoptosis signal-regulating kinase 1 (ASK1), an upstream activator of the JNK and p38 MAPK signaling pathways (8). Their alterations have been implicated in cardiovascular diseases (9), diabetes (10), hepatic and renal diseases (11), Alzheimer disease (12), Parkinson disease (13), and rheumatoid arthritis (14). Some human cancers show greatly increased Trx expression (15,16), indicating a potential role for Trx in tumorigenesis.…”

mentioning

confidence: 99%

NMR Structure of Carcinoscorpius rotundicauda Thioredoxin-related Protein 16 and Its Role in Regulating Transcription Factor NF-κB Activity

Giri

Fan

Shanmugam

et al. 2012

Journal of Biological Chemistry

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Background: Cr-TRP16 is a thioredoxin like protein that regulates NF-B activity. Results: NMR structure of Cr-TRP16, along with its regulation of NF-B activity, is reported. Conclusion: Our findings elucidate molecular mechanism by which NF-B activation is regulated through Cr-TRP16. Significance: This study helps further in understanding the interactions of Trxs and Trx-like proteins with other metabolic pathways and will lead to promising therapeutic development.

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Understanding the molecular causes of Parkinson's disease

Cited by 284 publications

References 87 publications

Proteomics-based safety evaluation of multi-walled carbon nanotubes

Proteomics-based safety evaluation of multi-walled carbon nanotubes

Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP

NMR Structure of Carcinoscorpius rotundicauda Thioredoxin-related Protein 16 and Its Role in Regulating Transcription Factor NF-κB Activity

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