Heat Shock Protein 70 Reduces α‐Synuclein‐Induced Predegenerative Neuronal Dystrophy in the α‐Synuclein Viral Gene Transfer Rat Model of Parkinson's Disease

It has become increasingly evident that the nigrostriatal degeneration associated with Parkinson's disease initiates at the level of the axonal terminals in the putamen, and this nigrostriatal terminal dystrophy is either caused or exacerbated by the presence of α‐synuclein immunopositive neuronal inclusions. Therefore, strategies aimed at reducing α‐synuclein‐induced early neuronal dystrophy may slow or halt the progression to overt nigrostriatal neurodegeneration. Thus, this study sought to determine if adeno‐associated virus (AAV) mediated overexpression of two molecular chaperone heat shock proteins, namely Hsp27 or Hsp70, in the AAV‐α‐synuclein viral gene transfer rat model of Parkinson's disease could prevent α‐synuclein‐induced early neuronal pathology.

[1]  J. Brodsky,et al.  Synthesis and initial evaluation of YM-08, a blood-brain barrier permeable derivative of the heat shock protein 70 (Hsp70) inhibitor MKT-077, which reduces tau levels. , 2013, ACS chemical neuroscience.

[2]  G. Juhász,et al.  Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice , 2013, Cell Stress and Chaperones.

[3]  A. O’Doherty,et al.  The behavioural and neuropathological impact of intranigral AAV-α-synuclein is exacerbated by systemic infusion of the Parkinson's disease-associated pesticide, rotenone, in rats , 2013, Behavioural Brain Research.

[4]  L. Greensmith,et al.  Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy. , 2013, Brain : a journal of neurology.

[5]  C. Olanow,et al.  Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion‐Like Disorder? , 2013, Movement disorders : official journal of the Movement Disorder Society.

[6]  P. Aebischer,et al.  Use of viral vectors to create animal models for Parkinson's disease , 2012, Neurobiology of Disease.

[7]  J. Kordower,et al.  Alterations in axonal transport motor proteins in sporadic and experimental Parkinson's disease. , 2012, Brain : a journal of neurology.

[8]  A. O’Doherty,et al.  Development and characterisation of a novel rat model of Parkinson's disease induced by sequential intranigral administration of AAV-α-synuclein and the pesticide, rotenone , 2012, Neuroscience.

[9]  A. Björklund,et al.  Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons , 2012, Proceedings of the National Academy of Sciences.

[10]  J. Koren,et al.  Exploiting the Diversity of the Heat-Shock Protein Family for Primary and Secondary Tauopathy Therapeutics , 2011, Current neuropharmacology.

[11]  S. Brady,et al.  Heat shock protein 70 prevents both tau aggregation and the inhibitory effects of preexisting tau aggregates on fast axonal transport. , 2011, Biochemistry.

[12]  Ilona B. Bruinsma,et al.  Inhibition of α‐synuclein aggregation by small heat shock proteins , 2011, Proteins.

[13]  P. Brundin,et al.  A deadly spread: cellular mechanisms of α-synuclein transfer , 2011, Cell Death and Differentiation.

[14]  B. Hyman,et al.  Heat‐shock protein 70 modulates toxic extracellular α‐synuclein oligomers and rescues trans‐synaptic toxicity , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  J. Jankovic,et al.  Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial , 2010, The Lancet Neurology.

[16]  F. Barry,et al.  Potential of rat bone marrow-derived mesenchymal stem cells as vehicles for delivery of neurotrophins to the Parkinsonian rat brain , 2010, Brain Research.

[17]  A. Liou,et al.  Heat shock proteins: Cellular and molecular mechanisms in the central nervous system , 2010, Progress in Neurobiology.

[18]  J. Uney,et al.  HSP70 interacting protein prevents the accumulation of inclusions in polyglutamine disease. , 2010, Journal of neurochemistry.

[19]  Ted M. Dawson,et al.  Genetic Animal Models of Parkinson's Disease , 2010, Neuron.

[20]  F. Barry,et al.  Survival and Immunogenicity of Mesenchymal Stem Cells From the Green Fluorescent Protein Transgenic Rat in the Adult Rat Brain , 2010, Neurorehabilitation and neural repair.

[21]  Matthias Mueller,et al.  The HSP70 Molecular Chaperone Is Not Beneficial in a Mouse Model of α-synucleinopathy , 2010, PloS one.

[22]  Takeo Kato,et al.  Heat shock proteins as suppressors of accumulation of toxic prefibrillar intermediates and misfolded proteins in neurodegenerative diseases. , 2010, Current pharmaceutical biotechnology.

[23]  W. Le,et al.  Collective roles of molecular chaperones in protein degradation pathways associated with neurodegenerative diseases. , 2010, Current pharmaceutical biotechnology.

[24]  Yuyu Song,et al.  Axonal Transport Defects in Neurodegenerative Diseases , 2009, The Journal of Neuroscience.

[25]  C. Warren Olanow,et al.  Alterations in lysosomal and proteasomal markers in Parkinson's disease: Relationship to alpha-synuclein inclusions , 2009, Neurobiology of Disease.

[26]  Ole Isacson,et al.  Dynamic Changes in Presynaptic and Axonal Transport Proteins Combined with Striatal Neuroinflammation Precede Dopaminergic Neuronal Loss in a Rat Model of AAV α-Synucleinopathy , 2009, The Journal of Neuroscience.

[27]  J. Trojanowski,et al.  Interactions between Hsp70 and the hydrophobic core of alpha-synuclein inhibit fibril assembly. , 2008, Biochemistry.

[28]  H. Waterham,et al.  Plasmalogens participate in very-long-chain fatty acid-induced pathology. , 2008, Brain : a journal of neurology.

[29]  S. Lindquist,et al.  Hsp104 antagonizes alpha-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease. , 2008, The Journal of clinical investigation.

[30]  J. Schulz,et al.  Tat‐Hsp70 protects dopaminergic neurons in midbrain cultures and in the substantia nigra in models of Parkinson’s disease , 2008, Journal of neurochemistry.

[31]  Bradley T. Hyman,et al.  Formation of Toxic Oligomeric α-Synuclein Species in Living Cells , 2008, PloS one.

[32]  S. Tabrizi,et al.  Hsp27 overexpression in the R6/2 mouse model of Huntington's disease: chronic neurodegeneration does not induce Hsp27 activation. , 2007, Human molecular genetics.

[33]  N. Déglon,et al.  Neuroprotection by Hsp104 and Hsp27 in lentiviral-based rat models of Huntington's disease. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[34]  B. Hyman,et al.  Small Heat Shock Proteins Protect Against α-Synuclein-Induced Toxicity and Aggregation , 2006 .

[35]  Hui Zhou,et al.  Heat shock protein 70 inhibits alpha-synuclein fibril formation via interactions with diverse intermediates. , 2006, Journal of molecular biology.

[36]  J. C. Smith,et al.  Isoflurane leakage from non-rebreathing rodent anaesthesia circuits: comparison of emissions from conventional and modified ports , 2006, Laboratory animals.

[37]  M. Tytell Release of heat shock proteins (Hsps) and the effects of extracellular Hsps on neural cells and tissues , 2005, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[38]  C. Dobson,et al.  Heat Shock Protein 70 Inhibits α-Synuclein Fibril Formation via Preferential Binding to Prefibrillar Species* , 2005, Journal of Biological Chemistry.

[39]  Bin Zhang,et al.  Axonal transport defects: a common theme in neurodegenerative diseases , 2005, Acta Neuropathologica.

[40]  Philippe Amouyel,et al.  α-synuclein locus duplication as a cause of familial Parkinson's disease , 2004, The Lancet.

[41]  J. Nylandsted,et al.  Heat Shock Protein 70 Promotes Cell Survival by Inhibiting Lysosomal Membrane Permeabilization , 2004, The Journal of experimental medicine.

[42]  Jochen Klucken,et al.  Hsp70 Reduces α-Synuclein Aggregation and Toxicity* , 2004, Journal of Biological Chemistry.

[43]  D. Latchman,et al.  HSP27 but not HSP70 has a potent protective effect against α‐synuclein‐induced cell death in mammalian neuronal cells , 2004, Journal of neurochemistry.

[44]  J. Hoenicka,et al.  The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia , 2004, Annals of neurology.

[45]  Matthew J. Farrer,et al.  Comparison of kindreds with parkinsonism and α‐synuclein genomic multiplications , 2004 .

[46]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[47]  G. Kroemer,et al.  Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor , 2003, Oncogene.

[48]  S. Borkan,et al.  HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells. , 2003, American journal of physiology. Cell physiology.

[49]  John T. Finn,et al.  Axonal Self-Destruction and Neurodegeneration , 2002, Science.

[50]  D. Rubinsztein,et al.  Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. , 2002, Human molecular genetics.

[51]  M. Sherman,et al.  Hsp72 and Stress Kinase c-jun N-Terminal Kinase Regulate the Bid-Dependent Pathway in Tumor Necrosis Factor-Induced Apoptosis , 2002, Molecular and Cellular Biology.

[52]  A. Björklund,et al.  Parkinson-Like Neurodegeneration Induced by Targeted Overexpression of α-Synuclein in the Nigrostriatal System , 2002, The Journal of Neuroscience.

[53]  John Q. Trojanowski,et al.  Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease , 2001, Science.

[54]  Josef M. Penninger,et al.  Heat-shock protein 70 antagonizes apoptosis-inducing factor , 2001, Nature Cell Biology.

[55]  Emad S. Alnemri,et al.  Negative regulation of the Apaf-1 apoptosome by Hsp70 , 2000, Nature Cell Biology.

[56]  Dick D. Mosser,et al.  Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome , 2000, Nature Cell Biology.

[57]  L. Mucke,et al.  Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. , 2000, Science.

[58]  D. Grimm,et al.  Novel tools for production and purification of recombinant adenoassociated virus vectors. , 1998, Human gene therapy.

[59]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[60]  D. Yellon,et al.  Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. , 1995, The Journal of clinical investigation.

[61]  B. Hyman,et al.  Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation. , 2006, Biochemical and biophysical research communications.

[62]  H. Lipp,et al.  Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[63]  M. Farrer,et al.  Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. , 2004, Annals of neurology.

[64]  B. Hyman,et al.  Hsp70 Reduces alpha-Synuclein Aggregation and Toxicity. , 2004, The Journal of biological chemistry.

[65]  Philippe Amouyel,et al.  Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. , 2004, Lancet.

[66]  A. Singleton,et al.  alpha-Synuclein locus triplication causes Parkinson's disease. , 2003, Science.

[67]  J. Trojanowski,et al.  Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. , 2002, Science.

[68]  R. Krüger,et al.  Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. , 1998, Nature genetics.

[69]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.