Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons
Dysfunction of the ubiquitin‐proteasomal system (UPS) has been implicated in the pathogenesis of Parkinson's disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinson's disease pathology in rodents. We administered a syn...
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| Published in | Annals of neurology Vol. 60; no. 2; pp. 253 - 255 |
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| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
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Wiley Subscription Services, Inc., A Wiley Company
01.08.2006
Willey-Liss |
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| Abstract | Dysfunction of the ubiquitin‐proteasomal system (UPS) has been implicated in the pathogenesis of Parkinson's disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinson's disease pathology in rodents. We administered a synthetic, specific UPS inhibitor (PSI) subcutaneously to rats and quantified substantia nigral tyrosine hydroxylase–positive dopaminergic neurons by stereology. PSI caused a 15% decrease in UPS activity at 2 weeks and a 42% reduction in substantia nigra pars compacta tyrosine hydroxylase–positive neurons at 8 weeks. Systemic inhibition of the UPS warrants further evaluation as a means to model Parkinson's disease. Ann Neurol 2006;60:253–255 |
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| AbstractList | Dysfunction of the ubiquitin‐proteasomal system (UPS) has been implicated in the pathogenesis of Parkinson's disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinson's disease pathology in rodents. We administered a synthetic, specific UPS inhibitor (PSI) subcutaneously to rats and quantified substantia nigral tyrosine hydroxylase–positive dopaminergic neurons by stereology. PSI caused a 15% decrease in UPS activity at 2 weeks and a 42% reduction in substantia nigra pars compacta tyrosine hydroxylase–positive neurons at 8 weeks. Systemic inhibition of the UPS warrants further evaluation as a means to model Parkinson's disease. Ann Neurol 2006;60:253–255 Dysfunction of the ubiquitin-proteasomal system (UPS) has been implicated in the pathogenesis of Parkinson's disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinson's disease pathology in rodents. We administered a synthetic, specific UPS inhibitor (PSI) subcutaneously to rats and quantified substantia nigral tyrosine hydroxylase-positive dopaminergic neurons by stereology. PSI caused a 15% decrease in UPS activity at 2 weeks and a 42% reduction in substantia nigra pars compacta tyrosine hydroxylase-positive neurons at 8 weeks. Systemic inhibition of the UPS warrants further evaluation as a means to model Parkinson's disease. |
| Author | Cleeter, Michael W. J. Cooper, J. Mark Workman, Jane M. King, Rosalind H. M. Schapira, Anthony H. V. Muddle, John R. |
| Author_xml | – sequence: 1 givenname: Anthony H. V. surname: Schapira fullname: Schapira, Anthony H. V. email: schapira@medsch.ucl.ac.uk organization: University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom – sequence: 2 givenname: Michael W. J. surname: Cleeter fullname: Cleeter, Michael W. J. organization: University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom – sequence: 3 givenname: John R. surname: Muddle fullname: Muddle, John R. organization: University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom – sequence: 4 givenname: Jane M. surname: Workman fullname: Workman, Jane M. organization: University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom – sequence: 5 givenname: J. Mark surname: Cooper fullname: Cooper, J. Mark organization: University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom – sequence: 6 givenname: Rosalind H. M. surname: King fullname: King, Rosalind H. M. organization: University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom |
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| Keywords | Nervous system diseases Oxidoreductases Tyrosine 3-monooxygenase Enzyme Cell death |
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| References_xml | – volume: 272 start-page: 13437 year: 1997 end-page: 13445 article-title: Lactacystin and clasto‐lactacystin beta‐lactone modify multiple proteasome beta‐subunits and inhibit intracellular protein degradation and major histocompatibility complex class I antigen presentation publication-title: J Biol Chem – volume: 54 start-page: 30 year: 1991 end-page: 33 article-title: The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method publication-title: J Neurol Neurosurg Psychiatry – volume: 57 start-page: 931 year: 1993 end-page: 941 article-title: Chronic nicotine treatment counteracts nigral cell loss induced by a partial mesodiencephalic hemitransection: an analysis of the total number and mean volume of neurons and glia in substantia nigra of the male rat publication-title: Neuroscience – volume: 60 start-page: 260 year: 2006 end-page: 264 article-title: Proteasome inhibition and Parkinson's disease modeling publication-title: Ann Neurol – volume: 60 start-page: 243 year: 2006 end-page: 247 article-title: The proteasome inhibitor‐induced model of Parkinson's disease publication-title: Ann Neurol – volume: 60 start-page: 256 year: 2006 end-page: 260 article-title: Lack of nigrostriatal pathology in a rat model of proteosome inhibition publication-title: Ann Neurol – volume: 306 start-page: 89 year: 2001 end-page: 92 article-title: SHIRPA, a protocol for behavioral assessment: validation for longitudinal study of neurological dysfunction in mice publication-title: Neurosci Lett – volume: 56 start-page: 149 year: 2004 end-page: 162 article-title: Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease publication-title: Ann Neurol – volume: 134 start-page: 127 issue: pt 2 year: 1984 end-page: 136 article-title: The unbiased estimation of number and sizes of arbitrary particles using the disector publication-title: J Microsc – volume: 60 start-page: 248 year: 2006 end-page: 252 article-title: Reproducible nigral cell loss after systemic proteasomal inhibitor administration to rats publication-title: Ann Neurol – volume: 302 start-page: 819 year: 2003 end-page: 822 article-title: Molecular pathways of neurodegeneration in Parkinson's disease publication-title: Science – volume: 60 start-page: 158 year: 2006 end-page: 161 article-title: The proteosomal inhibition model of Parkinson's disease: “boon or bust”? publication-title: Ann Neurol – year: 1998 – volume: 60 start-page: 264 year: 2006 end-page: 268 article-title: Failure of proteasome inhibitor administration to provide a model of Parkinson's disease in rats and monkeys publication-title: Ann Neurol – volume: 8 start-page: 739 year: 2001 end-page: 758 article-title: Proteasome inhibitors: from research tools to drug candidates publication-title: Chem Biol – volume: 60 start-page: 256 year: 2006 ident: 10.1002/ana.20934-BIB10 article-title: Lack of nigrostriatal pathology in a rat model of proteosome inhibition publication-title: Ann Neurol doi: 10.1002/ana.20938 contributor: fullname: Manning-Boğ – volume: 60 start-page: 264 year: 2006 ident: 10.1002/ana.20934-BIB12 article-title: Failure of proteasome inhibitor administration to provide a model of Parkinson's disease in rats and monkeys publication-title: Ann Neurol doi: 10.1002/ana.20935 contributor: fullname: Kordower – volume-title: The rat brain in stereotactic coordinates year: 1998 ident: 10.1002/ana.20934-BIB3 contributor: fullname: Paxinos – volume: 8 start-page: 739 year: 2001 ident: 10.1002/ana.20934-BIB15 article-title: Proteasome inhibitors: from research tools to drug candidates publication-title: Chem Biol doi: 10.1016/S1074-5521(01)00056-4 contributor: fullname: Kisselev – volume: 60 start-page: 260 year: 2006 ident: 10.1002/ana.20934-BIB11 article-title: Proteasome inhibition and Parkinson's disease modeling publication-title: Ann Neurol doi: 10.1002/ana.20937 contributor: fullname: Bové – volume: 134 start-page: 127 issue: pt 2 year: 1984 ident: 10.1002/ana.20934-BIB6 article-title: The unbiased estimation of number and sizes of arbitrary particles using the disector publication-title: J Microsc doi: 10.1111/j.1365-2818.1984.tb02501.x contributor: fullname: Sterio – volume: 306 start-page: 89 year: 2001 ident: 10.1002/ana.20934-BIB2 article-title: SHIRPA, a protocol for behavioral assessment: validation for longitudinal study of neurological dysfunction in mice publication-title: Neurosci Lett doi: 10.1016/S0304-3940(01)01885-7 contributor: fullname: Rogers – volume: 60 start-page: 158 year: 2006 ident: 10.1002/ana.20934-BIB13 article-title: The proteosomal inhibition model of Parkinson's disease: “boon or bust”? publication-title: Ann Neurol doi: 10.1002/ana.20939 contributor: fullname: Lang – volume: 60 start-page: 243 year: 2006 ident: 10.1002/ana.20934-BIB8 article-title: The proteasome inhibitor-induced model of Parkinson's disease publication-title: Ann Neurol doi: 10.1002/ana.20936 contributor: fullname: McNaught – volume: 56 start-page: 149 year: 2004 ident: 10.1002/ana.20934-BIB1 article-title: Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease publication-title: Ann Neurol doi: 10.1002/ana.20186 contributor: fullname: McNaught – volume: 302 start-page: 819 year: 2003 ident: 10.1002/ana.20934-BIB14 article-title: Molecular pathways of neurodegeneration in Parkinson's disease publication-title: Science doi: 10.1126/science.1087753 contributor: fullname: Dawson – volume: 272 start-page: 13437 year: 1997 ident: 10.1002/ana.20934-BIB7 article-title: Lactacystin and clasto-lactacystin beta-lactone modify multiple proteasome beta-subunits and inhibit intracellular protein degradation and major histocompatibility complex class I antigen presentation publication-title: J Biol Chem doi: 10.1074/jbc.272.20.13437 contributor: fullname: Craiu – volume: 60 start-page: 248 year: 2006 ident: 10.1002/ana.20934-BIB9 article-title: Reproducible nigral cell loss after systemic proteasomal inhibitor administration to rats publication-title: Ann Neurol doi: 10.1002/ana.20932 contributor: fullname: Zeng – volume: 57 start-page: 931 year: 1993 ident: 10.1002/ana.20934-BIB4 article-title: Chronic nicotine treatment counteracts nigral cell loss induced by a partial mesodiencephalic hemitransection: an analysis of the total number and mean volume of neurons and glia in substantia nigra of the male rat publication-title: Neuroscience doi: 10.1016/0306-4522(93)90039-I contributor: fullname: Janson – volume: 54 start-page: 30 year: 1991 ident: 10.1002/ana.20934-BIB5 article-title: The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method publication-title: J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp.54.1.30 contributor: fullname: Pakkenberg |
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| SubjectTerms | Animals Behavior, Animal - drug effects Biological and medical sciences Brain Chemistry - drug effects Chymotrypsin - metabolism Cysteine Proteinase Inhibitors - pharmacology Development. Senescence. Regeneration. Transplantation Fundamental and applied biological sciences. Psychology Grooming - drug effects Hand Strength Isolated neuron and nerve. Neuroglia Medical sciences Motor Activity - drug effects Muscle Tonus - drug effects Neurology Neurons - enzymology Oligopeptides - pharmacology Postural Balance - drug effects Proteasome Endopeptidase Complex - drug effects Rats Rats, Sprague-Dawley Reflex - drug effects Substantia Nigra - cytology Substantia Nigra - enzymology Tyrosine 3-Monooxygenase - metabolism Vertebrates: nervous system and sense organs Weight Gain - drug effects |
| Title | Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons |
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