Parkinson Disease: Plun-Favreau H

Fitzgerald JC, Plun-Favreau H. · Department of Molecular Neuroscience, Institute of Neurology, University College London, UK. · FEBS J. · Pubmed #19021753 No free full text.

Abstract: Rare, inherited mutations causing familial forms of Parkinson's disease have provided insight into the molecular mechanisms that underlie the genetic and sporadic forms of this disease. Loss of protein function resulting from autosomal-recessive mutations in PTEN-induced putative kinase 1 (PINK1), Parkin and DJ-1 has been linked to mitochondrial dysfunction, accumulation of abnormal and misfolded proteins, impaired protein clearance and oxidative stress. Accumulating evidence suggests that wild-type PINK1, Parkin and DJ-1 may be key components of neuroprotective signalling cascades that run in parallel, interact via cross talk or converge in a common pathway.

Plun-Favreau H, Gandhi S, Wood-Kaczmar A, Deas E, Yao Z, Wood NW. · Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK. · Ann N Y Acad Sci. · Pubmed #19076428 No free full text.

Abstract: Parkinson's disease (PD) is a common, disabling, neurodegenerative disease. Our knowledge of the molecular events leading to PD is being greatly enhanced by the study of relatively rare familial form of the disease. Nevertheless, the pathways leading from the genetic mutations to nigral cell degeneration and the other features in PD remain poorly understood. The identification of PINK1, a mitochondrial putative protein kinase, has helped understand the pathophysiology of mitochondria and their potential role in PD. Mutations in PINK1 are associated with the PARK6 autosomal recessive, early-onset, PD-susceptibility locus. Point mutations in another mitochondrial protein, HtrA2, are a susceptibility factor for PD (PARK13 locus). We report here the results of investigations into the interactors and pathways of these two mitochondrial molecules (PINK1 and HtrA2) in a range of models and human PD tissue.

Moisoi N, Klupsch K, Fedele V, East P, Sharma S, Renton A, Plun-Favreau H, Edwards RE, Teismann P, Esposti MD, Morrison AD, Wood NW, Downward J, Martins LM. · Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester LE1 9HN, UK. · Cell Death Differ. · Pubmed #19023330 No free full text.

Abstract: Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here, we demonstrate that loss of HtrA2 results in transcriptional upregulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson's disease patients' brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases.

Plun-Favreau H, Hardy J. · Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom. · Proc Natl Acad Sci U S A. · Pubmed #18687903 links to  free full text

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Plun-Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, Frith D, Harvey K, Deas E, Harvey RJ, McDonald N, Wood NW, Martins LM, Downward J. · Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. · Nat Cell Biol. · Pubmed #17906618 No free full text.

Abstract: In mice, targeted deletion of the serine protease HtrA2 (also known as Omi) causes mitochondrial dysfunction leading to a neurodegenerative disorder with parkinsonian features. In humans, point mutations in HtrA2 are a susceptibility factor for Parkinson's disease (PARK13 locus). Mutations in PINK1, a putative mitochondrial protein kinase, are associated with the PARK6 autosomal recessive locus for susceptibility to early-onset Parkinson's disease. Here we determine that HtrA2 interacts with PINK1 and that both are components of the same stress-sensing pathway. HtrA2 is phosphorylated on activation of the p38 pathway, occurring in a PINK1-dependent manner at a residue adjacent to a position found mutated in patients with Parkinson's disease. HtrA2 phosphorylation is decreased in brains of patients with Parkinson's disease carrying mutations in PINK1. We suggest that PINK1-dependent phosphorylation of HtrA2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress.

Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Müller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Krüger R. · Center of Neurology and Hertie-Institute for Clinical Brain Research, Leicester, UK. · Hum Mol Genet. · Pubmed #15961413 links to  free full text

Abstract: Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.