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Genetic findings in Parkinson's disease and translation into treatment: a leading role for mitochondria?

Bogaerts V, Theuns J, van Broeckhoven C - Genes Brain Behav. (2007)

Bottom Line: While current treatments temporarily alleviate symptoms, they do not halt disease progression.Here we summarize how the proteins identified through genetic research (alpha-synuclein, parkin, PINK1, DJ-1, LRRK2 and HTRA2) fit into and add to our current understanding of the role of mitochondrial dysfunction in PD.We highlight how these genetic findings provided us with suitable animal models and critically review how the gained insights will contribute to better therapies for PD.

View Article: PubMed Central - PubMed

Affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, University of Antwerpen, Antwerpen, Belgium.

ABSTRACT
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder and in most patients its aetiology remains unknown. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, and support a major role for mitochondrial dysfunction, which is also of significant importance to the common sporadic forms of PD. While current treatments temporarily alleviate symptoms, they do not halt disease progression. Drugs that target the underlying pathways to PD pathogenesis, including mitochondrial dysfunction, therefore hold great promise for neuroprotection in PD. Here we summarize how the proteins identified through genetic research (alpha-synuclein, parkin, PINK1, DJ-1, LRRK2 and HTRA2) fit into and add to our current understanding of the role of mitochondrial dysfunction in PD. We highlight how these genetic findings provided us with suitable animal models and critically review how the gained insights will contribute to better therapies for PD.

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Entry points for PD therapy involving mitochondria. Green boxes highlight potential neuroprotective drugs at their respective action levels, and dotted lines indicate premature termination of clinical trials for promising neuroprotective drugs. Abbreviations: Cyt C, cytochrome c; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MKK4/7, MAPK kinases 4/7; P, phosphorylated.
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fig05: Entry points for PD therapy involving mitochondria. Green boxes highlight potential neuroprotective drugs at their respective action levels, and dotted lines indicate premature termination of clinical trials for promising neuroprotective drugs. Abbreviations: Cyt C, cytochrome c; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MKK4/7, MAPK kinases 4/7; P, phosphorylated.

Mentions: The neuroprotective drugs include dopamine agonists and MAO-B inhibitors, which are already used for years to improve symptoms in the early stages of PD. Based on our current understanding of PD pathogenesis and mitochondria-related mechanisms of cell death, neuroprotective drugs can be divided into drugs that (1) attenuate mitochondrial apoptosis, (2) reduce oxidative stress in mitochondria or (3) directly target mitochondrial function (Fig. 5).


Genetic findings in Parkinson's disease and translation into treatment: a leading role for mitochondria?

Bogaerts V, Theuns J, van Broeckhoven C - Genes Brain Behav. (2007)

Entry points for PD therapy involving mitochondria. Green boxes highlight potential neuroprotective drugs at their respective action levels, and dotted lines indicate premature termination of clinical trials for promising neuroprotective drugs. Abbreviations: Cyt C, cytochrome c; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MKK4/7, MAPK kinases 4/7; P, phosphorylated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2268956&req=5

fig05: Entry points for PD therapy involving mitochondria. Green boxes highlight potential neuroprotective drugs at their respective action levels, and dotted lines indicate premature termination of clinical trials for promising neuroprotective drugs. Abbreviations: Cyt C, cytochrome c; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MKK4/7, MAPK kinases 4/7; P, phosphorylated.
Mentions: The neuroprotective drugs include dopamine agonists and MAO-B inhibitors, which are already used for years to improve symptoms in the early stages of PD. Based on our current understanding of PD pathogenesis and mitochondria-related mechanisms of cell death, neuroprotective drugs can be divided into drugs that (1) attenuate mitochondrial apoptosis, (2) reduce oxidative stress in mitochondria or (3) directly target mitochondrial function (Fig. 5).

Bottom Line: While current treatments temporarily alleviate symptoms, they do not halt disease progression.Here we summarize how the proteins identified through genetic research (alpha-synuclein, parkin, PINK1, DJ-1, LRRK2 and HTRA2) fit into and add to our current understanding of the role of mitochondrial dysfunction in PD.We highlight how these genetic findings provided us with suitable animal models and critically review how the gained insights will contribute to better therapies for PD.

View Article: PubMed Central - PubMed

Affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, University of Antwerpen, Antwerpen, Belgium.

ABSTRACT
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder and in most patients its aetiology remains unknown. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, and support a major role for mitochondrial dysfunction, which is also of significant importance to the common sporadic forms of PD. While current treatments temporarily alleviate symptoms, they do not halt disease progression. Drugs that target the underlying pathways to PD pathogenesis, including mitochondrial dysfunction, therefore hold great promise for neuroprotection in PD. Here we summarize how the proteins identified through genetic research (alpha-synuclein, parkin, PINK1, DJ-1, LRRK2 and HTRA2) fit into and add to our current understanding of the role of mitochondrial dysfunction in PD. We highlight how these genetic findings provided us with suitable animal models and critically review how the gained insights will contribute to better therapies for PD.

Show MeSH
Related in: MedlinePlus