Parkinson Disease: Latchman DS

Yang YX, Wood NW, Latchman DS. · Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK. · Neuroreport. · Pubmed #19151598 No free full text.

Abstract: Parkinson's disease is the second most common neurodegenerative disorder and remains incurable. Considerable progress has been made in understanding the molecular mechanisms of this disease, in particular, a distinct set of genes have emerged, whose dysfunctional regulation is strongly associated with the condition. These genes include alpha-synuclein, parkin, PTEN induced Putative Kinase 1 (PINK1), DJ-1, Leucine Rich Repeat Kinase 2 (LRRK2) and ATP13A2. Here we discuss what has been learnt in the study of these genes and how these genes may contribute to the pathogenesis of Parkinson's disease through different molecular pathways, and consider how these pathways might converge to lead to the onset of Parkinson's disease.

Latchman DS. · University of London, Birkbeck, London, UK. · Curr Opin Mol Ther. · Pubmed #16248276 No free full text.

Abstract: Vectors based on herpes simplex virus (HSV) are being developed for use in human neurodegenerative diseases and cancer. In neurodegenerative disease, this involves the use of highly disabled, non-replicating HSV vectors engineered to carry a therapeutic gene. In contrast, the use of HSV vectors in cancer involves partially disabled viruses that can replicate in dividing cells but not in non-dividing cells and therefore have an oncolytic effect. Both these approaches have produced promising results in cell culture and animal models. Moreover, phase I clinical trials have demonstrated the safety of HSV vectors and their possible efficacy in otherwise untreatable cancers.

Latchman DS. · Institute of Child Health, University College London, London WC1N 1EH, United Kingdom. · Int Rev Neurobiol. · Pubmed #12968539 No free full text.

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Latchman DS, Coffin RS. · Institute of Child Health, University College London, UK. · Rev Neurosci. · Pubmed #11236066 No free full text.

Abstract: The ability of transplanted neurons from aborted foetuses to produce some therapeutic benefit in Parkinson's disease makes this disease an obvious target for the development of gene therapy procedures which involve delivering the same factors as are provided by the foetal neurons but using a reagent which could be produced in large amounts in a standardised manner. This approach could involve both the delivery of the gene encoding tyrosine hydroxylase to boost dopamine production or the delivery of genes encoding neurotrophic factors such as GDNF to promote the survival of dopaminergic neurons. A variety of different viral and non-viral methods for achieving such gene delivery has been described. These are discussed together with the particular advantages of herpes simplex virus-based vectors which have the potential to deliver multiple therapeutic genes in a single virus vector.

Latchman DS. · Department of Molecular Pathology, Windeyer Institute of Medical Sciences, University College London, U.K. · Biochem Soc Trans. · Pubmed #10830115 No free full text.

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Latchman DS. · Department of Molecular Pathology, Windeyer Institute of Medical Sciences, University College London, UK. · J R Soc Med. · Pubmed #10703493 links to  free full text

This publication has no abstract.

Latchman DS, Coffin RS. · Department of Molecular Pathology, Windeyer Institute of Medical Sciences, University College London, UK. · Mov Disord. · Pubmed #10634236 No free full text.

Abstract: Parkinson's disease is an obvious target for the development of gene therapy procedures which could involve both the delivery of the gene encoding tyrosine hydroxylase to boost dopamine production or the delivery of genes encoding neurotrophic factors such as GDNF to promote the survival of dopaminergic neurons. A variety of different viral and nonviral methods for achieving such gene delivery are described together with the particular advantages of herpes simplex virus-based vectors which have the potential to deliver multiple therapeutic genes in a single virus vector.

Sleiman PM, Healy DG, Muqit MM, Yang YX, Van Der Brug M, Holton JL, Revesz T, Quinn NP, Bhatia K, Diss JK, Lees AJ, Cookson MR, Latchman DS, Wood NW. · Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK. · Neurosci Lett. · Pubmed #19429166 No free full text.

Abstract: OBJECTIVE: We performed a mutation screen of NR4A2 (also known as NURR1) in 409 Parkinson's disease (PD) patients. We identified a novel single base substitution in the 5'UTR of the NR4A2 (also known as NURR1) gene (c.-309C>T). RESULTS: We have performed expression studies in neuronal cell lines showing that the c.-309C>T mutation reduces NR4A2 mRNA expression in vitro. We have confirmed this finding in vivo by performing allele specific real-time PCR from brain tissue harbouring the 309C>T mutation and show a 3.48+/-1.62 fold reduction in mRNA expression of the mutant allele compared to wild-type. In addition we have undertaken genome wide expression analysis of the mutant NR4A2 brain and shown underexpressed genes were significantly enriched for gene ontology categories in nervous system development and synaptic transmission and overexpressed genes were enriched for unfolded protein response and morphogenesis. Lastly we have shown that the c.-309C>T mutation abrogates the protective effect of wild-type NR4A2 against apoptopic stress. CONCLUSIONS: Our findings indicate the c.-309C>T mutation reduces NR4A2 expression resulting in the downregulation of genes involved in the development and maintenance of the nervous system and synaptic transmission. These downregulated pathways contained genes known to be transactivated by NR4A2 and were not disrupted in idiopathic PD brain suggesting causality of the mutation.

Yang YX, Latchman DS. · Medical Molecular Biology Unit, Institute of Child Health, University College London, UK. · Neuroreport. · Pubmed #18463503 No free full text.

Abstract: Parkinson's disease is one of the most common neurodegenerative disorders and still remains incurable. The condition is linked to mutations and alterations in expression in several genes, in particular that encoding alpha-synuclein. Mutations in Nurr1 leading to a reduction in expression were also found to lead to Parkinson's disease. In view of the importance of gene regulation in Parkinson's disease, we examined the effect of changes in Nurr1 expression on alpha-synuclein expression. Nurr1 was shown to be involved in the regulation of alpha-synuclein, as decreased expression of Nurr1, which has been found in Parkinson's disease patients with Nurr1 mutations, was shown to transcriptionally increase alpha-synuclein expression.

Abou-Sleiman PM, Muqit MM, McDonald NQ, Yang YX, Gandhi S, Healy DG, Harvey K, Harvey RJ, Deas E, Bhatia K, Quinn N, Lees A, Latchman DS, Wood NW. · Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom. · Ann Neurol. · Pubmed #16969854 No free full text.

Abstract: OBJECTIVE: To investigate the significance of PINK1 mutations in sporadic Parkinson's disease (PD). METHODS: We determined the frequency of PINK1 mutations by direct sequencing in a large series of PD patients with apparently sporadic disease (n = 768). RESULTS: Twelve heterozygous mutations were identified, nine in PD patients and three in control subjects. INTERPRETATION: Given the difficulty in interpreting the pathogenic significance of the heterozygous mutations that have already been reported in parkin and DJ-1, we first determined the frequency of heterozygous PINK1 mutations in the general population by sequencing a large number of control subjects (n = 768), then subsequently assessed their functional significance by examining their effects on stress-induced alterations to the mitochondrial membrane potential (DeltaPsim). We demonstrate an enrichment of heterozygous mutations in sporadic PD patients compared with matched control subjects (1.2% in PD vs 0.4% in control subjects). Furthermore, we show that they adversely affect DeltaPsim in a similar way to the familial G309D mutation. Although it remains difficult to conclusively demonstrate the pathogenicity of heterozygous mutations, the results of this study and the previously reported subclinical nigrostriatal dysfunction in carriers of heterozygous PINK1 mutations suggest the possibility that these heterozygous mutations are a significant risk factor in the development of later onset PD.

Muqit MM, Abou-Sleiman PM, Saurin AT, Harvey K, Gandhi S, Deas E, Eaton S, Payne Smith MD, Venner K, Matilla A, Healy DG, Gilks WP, Lees AJ, Holton J, Revesz T, Parker PJ, Harvey RJ, Wood NW, Latchman DS. · Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK. · J Neurochem. · Pubmed #16805805 No free full text.

Abstract: Following our identification of PTEN-induced putative kinase 1 (PINK1) gene mutations in PARK6-linked Parkinson's disease (PD), we have recently reported that PINK1 protein localizes to Lewy bodies (LBs) in PD brains. We have used a cellular model system of LBs, namely induction of aggresomes, to determine how a mitochondrial protein, such as PINK1, can localize to aggregates. Using specific polyclonal antibodies, we firstly demonstrated that human PINK1 was cleaved and localized to mitochondria. We demonstrated that, on proteasome inhibition with MG-132, PINK1 and other mitochondrial proteins localized to aggresomes. Ultrastructural studies revealed that the mechanism was linked to the recruitment of intact mitochondria to the aggresome. Fractionation studies of lysates showed that PINK1 cleavage was enhanced by proteasomal stress in vitro and correlated with increased expression of the processed PINK1 protein in PD brain. These observations provide valuable insights into the mechanisms of LB formation in PD that should lead to a better understanding of PD pathogenesis.

Gandhi S, Muqit MM, Stanyer L, Healy DG, Abou-Sleiman PM, Hargreaves I, Heales S, Ganguly M, Parsons L, Lees AJ, Latchman DS, Holton JL, Wood NW, Revesz T. · Department of Molecular Neuroscience, Institute of Neurology University College London, London, UK. · Brain. · Pubmed #16702191 links to  free full text

Abstract: Parkinson's disease is a common incurable neurodegenerative disease whose molecular aetiology remains unclear. The identification of Mendelian genes causing rare familial forms of Parkinson's disease has revealed novel proteins and pathways that are likely to be relevant in the pathogenesis of sporadic Parkinson's disease. Recently, mutations in a novel gene, PINK1, encoding a 581 amino acid protein with both mitochondrial targeting and serine/threonine kinase domains, were identified as a cause of autosomal recessive parkinsonism. This provided important evidence for the role of the mitochondrial dysfunction and kinase pathways in neurodegeneration. In this study, we report the first characterization of the PINK1 protein in normal human and sporadic Parkinson's brains, in addition to Parkinson's cases with heterozygous PINK1 mutations. The possible role of the PINK1 protein was also assessed in a number of neurodegenerative diseases characterized by proteinaceous inclusions. For these studies, rabbit polyclonal antibodies were raised against two peptide sequences within the N-terminal hydrophilic loops of PINK1 protein. Using immunohistochemistry and western blotting we were able to demonstrate that PINK1 is a ubiquitous protein expressed throughout the human brain and it is found in all cell types showing a punctate cytoplasmic staining pattern consistent with mitochondrial localization. Fractionation studies of human and rat brain confirm that PINK1 is localized to the mitochondrial membranes. In addition, we show that PINK1 is detected in a proportion of Lewy bodies in cases of sporadic Parkinson's disease and Parkinson's disease associated with heterozygous mutations in the PINK1 gene, which are clinically and pathologically indistinguishable from the sporadic cases. PINK1 was absent in cortical Lewy bodies, in neurofibrillary tangles in Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, and in the glial and neuronal alpha-synuclein positive inclusions in multiple system atrophy. These studies provide for the first time in vivo morphological and biochemical evidence to support a mitochondrial localization of PINK1 and underpin the significance of mitochondrial dysfunction in the pathogenesis of nigral cell degeneration in Parkinson's disease.

Bandopadhyay R, Kingsbury AE, Muqit MM, Harvey K, Reid AR, Kilford L, Engelender S, Schlossmacher MG, Wood NW, Latchman DS, Harvey RJ, Lees AJ. · Reta Lila Weston Institute of Neurological Studies, Royal Free and UCL Medical School, The Windeyer Building, 46 Cleveland Street, London W1T 4JF, UK. · Neurobiol Dis. · Pubmed #15894486 No free full text.

Abstract: Lewy bodies (LBs) are the characteristic inclusions of Parkinson's disease brain but the mechanism responsible for their formation is obscure. Lewy bodies (LBs) are composed of a number of proteins of which alpha-synuclein (alpha-SYN) is a major constituent. In this study, we have investigated the distribution patterns of synphilin-1 and parkin proteins in control and sporadic PD brain tissue by immunohistochemistry (IH), immunoblotting, and immunoelectron microscopy (IEM). We demonstrate the presence of synphilin-1 and parkin in the central core of a majority of LBs using IH and IEM. Using IH, we show an overlapping distribution profile of the two proteins in central neurons. Additionally, we show sensitivity of both endogenous synphilin-1 and parkin to proteolytic dysfunction and their co-localization in aggresomes formed in response to the proteasome inhibitor MG-132. We confirm that synphilin-1 and parkin are components of majority of LBs in Parkinson's disease and that both proteins are susceptible to proteasomal degradation.

Parkinson EJ, Townsend PA, Stephanou A, Latchman DS, Eaton S, Pierro A. · Department of Paediatric Surgery, Institute of Child Health, London, England, UK. · J Pediatr Surg. · Pubmed #15137002 No free full text.

Abstract: BACKGROUND/PURPOSE: Moderate hypothermia throughout intestinal ischemia-reperfusion (IIR) injury reduces multiple organ dysfunction. Heat shock proteins (HSPs) have been shown to be protective against ischemia-reperfusion injury, and STAT (Signal Transducers and Activators of Transcription) proteins are pivotal determinants of the cellular response to reperfusion injury. The aim of this study is to investigate the mechanism of hypothermic protection during IIR. METHODS: Adult rats underwent intestinal ischemia-reperfusion (IIR), 60-minute ischemia and 60-minute reperfusion, or sham (120 minutes) at either normothermia or moderate hypothermia. Four groups of animals were studied: (1) normothermic sham (NS), (2) normothermic IIR (NIIR), (3) hypothermic sham (HS), and (4) hypothermic IIR (HIIR). Western blotting measured heat shock protein expression, phosphorylated (p-) and total (T-) hepatic STAT-1 and STAT-3. RESULTS: There were no differences in expression of HSPs 27, 47, 60, i70, c70, or 90 between any of the experimental groups. NIIR caused a significant increase in p-STAT-1 compared with normothermic sham (P <.05) and a highly significant increase in p-STAT-3 (P <.001), both these increases were completely abolished by moderate hypothermia (P <.01 v NIIR.) CONCLUSIONS: The protective effect of moderate hypothermia on liver is not mediated by HSP expression at this time-point. Hypothermia may act by decreasing hepatic STAT activation, supporting the potential therapeutic role of moderate hypothermia. Modulation of STAT activation may also provide novel therapeutic targets.

Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. · CSS IRCCS, Mendel Institute, viale Regina Margherita 261, 00198 Rome, Italy. · Science. · Pubmed #15087508 links to  free full text

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.

Muqit MM, Davidson SM, Payne Smith MD, MacCormac LP, Kahns S, Jensen PH, Wood NW, Latchman DS. · Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK. · Hum Mol Genet. · Pubmed #14645198 links to  free full text

Abstract: Parkinson's disease (PD) is characterized by loss of dopamine neurons in the substantia nigra and the presence of cytoplasmic inclusions known as Lewy bodies (LBs). Mutations in parkin cause autosomal recessive juvenile parkinsonism (AR-JP) that is distinct from sporadic PD by the general absence of LBs. Several studies have reported that parkin is present in LBs of sporadic PD but the role of parkin in LB formation is unclear. Aggresomes are perinuclear aggregates representing intracellular deposition of misfolded protein. LBs and aggresomes have been reported to share a common biogenesis. We have investigated the role of parkin in aggresome formation. In human SH-SY5Y neuroblastoma cells we observe that endogenous parkin is present in aggresomes induced by a variety of stresses including dopamine, proteosome inhibition and a pro-apoptopic stimulus. We show that vimentin is invariably collapsed around the aggresome but that the detection of ubiquitin is variable depending on the stress. We show that cells that stably over-express human wild-type parkin form fewer aggresomes upon stress compared to cells that express vector alone whereas over-expression of AR-JP causing mutants of parkin have no effect on stress-induced aggresome formation. Finally, we show that the prevention of aggresome formation by over-expression of wild-type parkin is not always associated with a beneficial effect on neuronal survival. Our findings suggest that parkin is important for aggresome formation in human neuronal cells and may lead to a better understanding of the biogenesis of LBs in sporadic PD.