A model of nitric oxide induced α-synuclein misfolding in Parkinson's disease

David K. Stone; Tomomi Kiyota; R. Lee Mosley; Howard E. Gendelman

doi:10.1016/j.neulet.2012.06.070

A model of nitric oxide induced α-synuclein misfolding in Parkinson's disease

David K. Stone, Tomomi Kiyota, R. Lee Mosley, Howard E. Gendelman

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

Inducible nitric oxide synthase (iNOS) upregulation and consequent NO formation are well-recognized neuroinflammatory responses associated with Parkinson's disease (PD). These contribute to nitrosative protein modifications affecting neuronal injury and cell death. Indeed, a pathobiologic signature for PD is Lewy body formation containing misfolded and aggregated forms of alpha-synuclein (α-syn). Moreover, nitration of α-syn promotes protein aggregation in disease. To model such pathological events, we constructed controllable iNOS and bicistronic α-syn-IRES-tTA adeno-associated virus (AAV) expression vectors. Transduction of iNOS and α-syn AAV constructs led to nitration of α-syn in neurons and overexpression of iNOS promoted protein aggregation. We posit that this AAV system mimics critical protein misfolding events associated with the pathogenesis of PD.

Original language	English (US)
Pages (from-to)	167-173
Number of pages	7
Journal	Neuroscience Letters
Volume	523
Issue number	2
DOIs	https://doi.org/10.1016/j.neulet.2012.06.070
State	Published - Aug 15 2012

Keywords

Adeno-associated virus
Alpha-synuclein
Atomic force microscopy
Nitration
Parkinson's disease

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neulet.2012.06.070

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title = "A model of nitric oxide induced α-synuclein misfolding in Parkinson's disease",

abstract = "Inducible nitric oxide synthase (iNOS) upregulation and consequent NO formation are well-recognized neuroinflammatory responses associated with Parkinson's disease (PD). These contribute to nitrosative protein modifications affecting neuronal injury and cell death. Indeed, a pathobiologic signature for PD is Lewy body formation containing misfolded and aggregated forms of alpha-synuclein (α-syn). Moreover, nitration of α-syn promotes protein aggregation in disease. To model such pathological events, we constructed controllable iNOS and bicistronic α-syn-IRES-tTA adeno-associated virus (AAV) expression vectors. Transduction of iNOS and α-syn AAV constructs led to nitration of α-syn in neurons and overexpression of iNOS promoted protein aggregation. We posit that this AAV system mimics critical protein misfolding events associated with the pathogenesis of PD.",

keywords = "Adeno-associated virus, Alpha-synuclein, Atomic force microscopy, Nitration, Parkinson's disease",

author = "Stone, {David K.} and Tomomi Kiyota and Mosley, {R. Lee} and Gendelman, {Howard E.}",

note = "Funding Information: The authors would like to thank Dr. Lyudmila Shlyakhtenko for assistance with AFM measurements; Dr. Stephen Bonasera, and Dr. Daniel Murman for their advice; and Dr. David G. Standaert and Dr. Ashley Harms for help with stereotaxic microinjections. We thank Alex Knesevic and Dr. Kathy Estes for their technical assistance. We also thank the University of Pennsylvania Gene Therapy Program for rAAV1 and helper plasmids used in these studies. This work was supported by the UNMC Graduate Studies Fellowship (to D.K.S.), National Institutes of Health Grants 5R01NS070190-02 (to R.L.M.), 1P01 DA028555 , 2R01 NS034239 , 2R37 NS36126 , P01 NS31492 , P20RR 15635 , P30 MH062261 , P01MH64570 and P01 NS43985 and the Carol Swarts Emerging Neuroscience Fund (to H.E.G.). ",

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AU - Stone, David K.

AU - Kiyota, Tomomi

AU - Mosley, R. Lee

AU - Gendelman, Howard E.

N1 - Funding Information: The authors would like to thank Dr. Lyudmila Shlyakhtenko for assistance with AFM measurements; Dr. Stephen Bonasera, and Dr. Daniel Murman for their advice; and Dr. David G. Standaert and Dr. Ashley Harms for help with stereotaxic microinjections. We thank Alex Knesevic and Dr. Kathy Estes for their technical assistance. We also thank the University of Pennsylvania Gene Therapy Program for rAAV1 and helper plasmids used in these studies. This work was supported by the UNMC Graduate Studies Fellowship (to D.K.S.), National Institutes of Health Grants 5R01NS070190-02 (to R.L.M.), 1P01 DA028555 , 2R01 NS034239 , 2R37 NS36126 , P01 NS31492 , P20RR 15635 , P30 MH062261 , P01MH64570 and P01 NS43985 and the Carol Swarts Emerging Neuroscience Fund (to H.E.G.).

PY - 2012/8/15

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N2 - Inducible nitric oxide synthase (iNOS) upregulation and consequent NO formation are well-recognized neuroinflammatory responses associated with Parkinson's disease (PD). These contribute to nitrosative protein modifications affecting neuronal injury and cell death. Indeed, a pathobiologic signature for PD is Lewy body formation containing misfolded and aggregated forms of alpha-synuclein (α-syn). Moreover, nitration of α-syn promotes protein aggregation in disease. To model such pathological events, we constructed controllable iNOS and bicistronic α-syn-IRES-tTA adeno-associated virus (AAV) expression vectors. Transduction of iNOS and α-syn AAV constructs led to nitration of α-syn in neurons and overexpression of iNOS promoted protein aggregation. We posit that this AAV system mimics critical protein misfolding events associated with the pathogenesis of PD.

AB - Inducible nitric oxide synthase (iNOS) upregulation and consequent NO formation are well-recognized neuroinflammatory responses associated with Parkinson's disease (PD). These contribute to nitrosative protein modifications affecting neuronal injury and cell death. Indeed, a pathobiologic signature for PD is Lewy body formation containing misfolded and aggregated forms of alpha-synuclein (α-syn). Moreover, nitration of α-syn promotes protein aggregation in disease. To model such pathological events, we constructed controllable iNOS and bicistronic α-syn-IRES-tTA adeno-associated virus (AAV) expression vectors. Transduction of iNOS and α-syn AAV constructs led to nitration of α-syn in neurons and overexpression of iNOS promoted protein aggregation. We posit that this AAV system mimics critical protein misfolding events associated with the pathogenesis of PD.

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KW - Nitration

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A model of nitric oxide induced α-synuclein misfolding in Parkinson's disease

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Keywords

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