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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Molecular Chaperones as Rational Drug Targets for Parkinson’s Disease Therapeutics</title>
<author><name sortKey="Kalia, S K" sort="Kalia, S K" uniqKey="Kalia S" first="S. K." last="Kalia">S. K. Kalia</name>
<affiliation><nlm:aff id="A1">MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kalia, L V" sort="Kalia, L V" uniqKey="Kalia L" first="L. V." last="Kalia">L. V. Kalia</name>
<affiliation><nlm:aff id="A1">MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mclean, P J" sort="Mclean, P J" uniqKey="Mclean P" first="P. J." last="Mclean">P. J. Mclean</name>
<affiliation><nlm:aff id="A1">MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">20942788</idno>
<idno type="pmc">3364514</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364514</idno>
<idno type="RBID">PMC:3364514</idno>
<date when="2010">2010</date>
<idno type="wicri:Area/Pmc/Corpus">000754</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000754</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Molecular Chaperones as Rational Drug Targets for Parkinson’s Disease Therapeutics</title>
<author><name sortKey="Kalia, S K" sort="Kalia, S K" uniqKey="Kalia S" first="S. K." last="Kalia">S. K. Kalia</name>
<affiliation><nlm:aff id="A1">MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kalia, L V" sort="Kalia, L V" uniqKey="Kalia L" first="L. V." last="Kalia">L. V. Kalia</name>
<affiliation><nlm:aff id="A1">MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mclean, P J" sort="Mclean, P J" uniqKey="Mclean P" first="P. J." last="Mclean">P. J. Mclean</name>
<affiliation><nlm:aff id="A1">MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">CNS & neurological disorders drug targets</title>
<idno type="ISSN">1871-5273</idno>
<idno type="eISSN">1996-3181</idno>
<imprint><date when="2010">2010</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
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</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P1">Parkinson’s disease is a neurodegenerative movement disorder that is caused, in part, by the loss of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia. The presence of intracellular protein aggregates, known as Lewy bodies and Lewy neurites, within the surviving nigral neurons is the defining neuropathological feature of the disease. Accordingly, the identification of specific genes mutated in families with Parkinson’s disease and of genetic susceptibility variants for idiopathic Parkinson’s disease has implicated abnormalities in proteostasis, or the handling and elimination of misfolded proteins, in the pathogenesis of this neurodegenerative disorder. Protein folding and the refolding of misfolded proteins are regulated by a network of interactive molecules, known as the chaperone system, which is composed of molecular chaperones and co-chaperones. The chaperone system is intimately associated with the ubiquitin-proteasome system and the autophagy-lysosomal pathway which are responsible for elimination of misfolded proteins and protein quality control. In addition to their role in proteostasis, some chaperone molecules are involved in the regulation of cell death pathways. Here we review the role of the molecular chaperones Hsp70 and Hsp90, and the co-chaperones Hsp40, BAG family members such as BAG5, CHIP and Hip in modulating neuronal death with a focus on dopaminergic neurodegeneration in Parkinson’s disease. We also review current progress in preclinical studies aimed at targetting the chaperone system to prevent neurodegeneration. Finally, we discuss potential future chaperone-based therapeutics for the symptomatic treatment and possible disease modification of Parkinson’s disease.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101269155</journal-id>
<journal-id journal-id-type="pubmed-jr-id">32874</journal-id>
<journal-id journal-id-type="nlm-ta">CNS Neurol Disord Drug Targets</journal-id>
<journal-id journal-id-type="iso-abbrev">CNS Neurol Disord Drug Targets</journal-id>
<journal-title-group><journal-title>CNS & neurological disorders drug targets</journal-title>
</journal-title-group>
<issn pub-type="ppub">1871-5273</issn>
<issn pub-type="epub">1996-3181</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">20942788</article-id>
<article-id pub-id-type="pmc">3364514</article-id>
<article-id pub-id-type="manuscript">NIHMS377913</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Molecular Chaperones as Rational Drug Targets for Parkinson’s Disease Therapeutics</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kalia</surname>
<given-names>S.K.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref rid="FN2" ref-type="author-notes">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kalia</surname>
<given-names>L.V.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref rid="FN2" ref-type="author-notes">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>McLean</surname>
<given-names>P.J.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref rid="FN1" ref-type="author-notes">*</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA</aff>
<aff id="A2"><label>2</label>
Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada</aff>
<aff id="A3"><label>3</label>
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada</aff>
<author-notes><corresp id="FN1"><label>*</label>
Address correspondence to this author at the Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114, 16<sup>th</sup>
Street, Charlestown, MA 02129, USA; Tel: 617-726-1263; Fax: 617-724-1480; <email>pmclean@partners.org</email>
</corresp>
<fn id="FN2" fn-type="equal"><label>†</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>17</day>
<month>5</month>
<year>2012</year>
</pub-date>
<pub-date pub-type="ppub"><month>12</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>31</day>
<month>5</month>
<year>2012</year>
</pub-date>
<volume>9</volume>
<issue>6</issue>
<fpage>741</fpage>
<lpage>753</lpage>
<permissions><copyright-statement>© 2010 Bentham Science Publishers</copyright-statement>
<copyright-year>2010</copyright-year>
</permissions>
<abstract><p id="P1">Parkinson’s disease is a neurodegenerative movement disorder that is caused, in part, by the loss of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia. The presence of intracellular protein aggregates, known as Lewy bodies and Lewy neurites, within the surviving nigral neurons is the defining neuropathological feature of the disease. Accordingly, the identification of specific genes mutated in families with Parkinson’s disease and of genetic susceptibility variants for idiopathic Parkinson’s disease has implicated abnormalities in proteostasis, or the handling and elimination of misfolded proteins, in the pathogenesis of this neurodegenerative disorder. Protein folding and the refolding of misfolded proteins are regulated by a network of interactive molecules, known as the chaperone system, which is composed of molecular chaperones and co-chaperones. The chaperone system is intimately associated with the ubiquitin-proteasome system and the autophagy-lysosomal pathway which are responsible for elimination of misfolded proteins and protein quality control. In addition to their role in proteostasis, some chaperone molecules are involved in the regulation of cell death pathways. Here we review the role of the molecular chaperones Hsp70 and Hsp90, and the co-chaperones Hsp40, BAG family members such as BAG5, CHIP and Hip in modulating neuronal death with a focus on dopaminergic neurodegeneration in Parkinson’s disease. We also review current progress in preclinical studies aimed at targetting the chaperone system to prevent neurodegeneration. Finally, we discuss potential future chaperone-based therapeutics for the symptomatic treatment and possible disease modification of Parkinson’s disease.</p>
</abstract>
<kwd-group><kwd>Bcl-2 associated athanogene (BAG) family</kwd>
<kwd>C-terminal Hsp70 interacting protein (CHIP)</kwd>
<kwd>chaperones</kwd>
<kwd>co-chaperones</kwd>
<kwd>heat shock protein (Hsp)</kwd>
<kwd>Hsp90 inhibitors</kwd>
<kwd>neurodegeneration</kwd>
<kwd>Parkinson’s disease</kwd>
</kwd-group>
<funding-group><award-group><funding-source country="United States">National Institute of Neurological Disorders and Stroke : NINDS</funding-source>
<award-id>R01 NS063963 || NS</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
</pmc>
</record>
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