Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log in
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE
PreviousNext
Articles, Neurobiology of Disease

Is Parkinson's Disease a Vesicular Dopamine Storage Disorder? Evidence from a Study in Isolated Synaptic Vesicles of Human and Nonhuman Primate Striatum

Christian Pifl, Alex Rajput, Harald Reither, Javier Blesa, Carmen Cavada, José A. Obeso, Ali H. Rajput and Oleh Hornykiewicz
Journal of Neuroscience 11 June 2014, 34 (24) 8210-8218; DOI: https://doi.org/10.1523/JNEUROSCI.5456-13.2014
Christian Pifl
1Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alex Rajput
2Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Harald Reither
1Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Javier Blesa
3Movement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clinica Universidad de Navarra, E31008 Pamplona, Spain, and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Javier Blesa
Carmen Cavada
4Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, E28049 Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
José A. Obeso
3Movement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clinica Universidad de Navarra, E31008 Pamplona, Spain, and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ali H. Rajput
2Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Oleh Hornykiewicz
1Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

This article has a correction. Please see:

  • Correction: Pifl et al., Is Parkinson's Disease a Vesicular Dopamine Storage Disorder? Evidence from a Study in Isolated Synaptic Vesicles of Human and Nonhuman Primate Striatum - November 25, 2015

Abstract

The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson's disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles where it is protected from metabolic breakdown. In the cytoplasm, however, free DA can give rise to formation of cytotoxic free radicals. Normally, the concentration of cytoplasmic DA is kept at a minimum by continuous pumping activity of the vesicular monoamine transporter (VMAT)2. Defects in handling of cytosolic DA by VMAT2 increase levels of DA-generated oxy radicals ultimately resulting in degeneration of DAergic neurons. Here, we isolated for the first time, DA storage vesicles from the striatum of six autopsied brains of PD patients and four controls and measured several indices of vesicular DA storage mechanisms. We found that (1) vesicular uptake of DA and binding of the VMAT2-selective label [3H]dihydrotetrabenazine were profoundly reduced in PD by 87–90% and 71–80%, respectively; (2) after correcting for DA nerve terminal loss, DA uptake per VMAT2 transport site was significantly reduced in PD caudate and putamen by 53 and 55%, respectively; (3) the VMAT2 transport defect appeared specific for PD as it was not present in Macaca fascicularis (7 MPTP and 8 controls) with similar degree of MPTP-induced nigrostriatal neurodegeneration; and (4) DA efflux studies and measurements of acidification in the vesicular preparations suggest that the DA storage impairment was localized at the VMAT2 protein itself. We propose that this VMAT2 defect may be an early abnormality promoting mechanisms leading to nigrostriatal DA neuron death in PD.

  • dopamine
  • Parkinson's disease
  • striatum
  • synaptic vesicles
  • VMAT2
View Full Text
Back to top

In this issue

The Journal of Neuroscience: 34 (24)
Journal of Neuroscience
Vol. 34, Issue 24
11 Jun 2014
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Advertising (PDF)
  • Ed Board (PDF)
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Is Parkinson's Disease a Vesicular Dopamine Storage Disorder? Evidence from a Study in Isolated Synaptic Vesicles of Human and Nonhuman Primate Striatum
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
Is Parkinson's Disease a Vesicular Dopamine Storage Disorder? Evidence from a Study in Isolated Synaptic Vesicles of Human and Nonhuman Primate Striatum
Christian Pifl, Alex Rajput, Harald Reither, Javier Blesa, Carmen Cavada, José A. Obeso, Ali H. Rajput, Oleh Hornykiewicz
Journal of Neuroscience 11 June 2014, 34 (24) 8210-8218; DOI: 10.1523/JNEUROSCI.5456-13.2014

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
Is Parkinson's Disease a Vesicular Dopamine Storage Disorder? Evidence from a Study in Isolated Synaptic Vesicles of Human and Nonhuman Primate Striatum
Christian Pifl, Alex Rajput, Harald Reither, Javier Blesa, Carmen Cavada, José A. Obeso, Ali H. Rajput, Oleh Hornykiewicz
Journal of Neuroscience 11 June 2014, 34 (24) 8210-8218; DOI: 10.1523/JNEUROSCI.5456-13.2014
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Keywords

  • dopamine
  • Parkinson's disease
  • striatum
  • synaptic vesicles
  • VMAT2

Responses to this article

Respond to this article

Jump to comment:

  • Re:DOPAL toxicity explains how vesicular dopamine defect leads to Parkinson disease
    Richard M. LoPachin
    Published on: 01 August 2014
  • Re:Vesicular Storage Defect
    Christian Pifl
    Published on: 07 July 2014
  • DOPAL toxicity explains how vesicular dopamine defect leads to Parkinson disease
    William J Burke
    Published on: 06 July 2014
  • Vesicular Storage Defect
    David S. Goldstein
    Published on: 27 June 2014
  • Published on: (1 August 2014)
    Page navigation anchor for Re:DOPAL toxicity explains how vesicular dopamine defect leads to Parkinson disease
    Re:DOPAL toxicity explains how vesicular dopamine defect leads to Parkinson disease
    • Richard M. LoPachin, Professor of Anesthesiology
    • Other Contributors:
      • Terrence Gavin

    Regarding the excellent paper by Pifl et al. and corresponding comments by Dr. Burke, we also agree that an increase in the cytosolic levels of the dopamine (DA) metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL), might play a role in the presynaptic toxicity of Parkinson's disease (PD). However, defining this potential role requires an understanding of the rather complex chemistry and toxicology of this metabolite....

    Show More

    Regarding the excellent paper by Pifl et al. and corresponding comments by Dr. Burke, we also agree that an increase in the cytosolic levels of the dopamine (DA) metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL), might play a role in the presynaptic toxicity of Parkinson's disease (PD). However, defining this potential role requires an understanding of the rather complex chemistry and toxicology of this metabolite. Specifically, DOPAL is an unstable non-conjugated aldehyde that will undergo auto-oxidation to quinone derivatives. These derivatives are highly reactive soft electrophiles that preferentially form adducts with soft nucleophilic sulfhydryl thiolates on cysteine residues. Quinone adduction is inhibitory since these specialized anionic thiolate sites are found in pKa-lowering microenvironments that regulate the activities of presynaptic transporters and enzymes; e.g., Cys264 of N- ethylmaleimide sensitive factor (NSF); Cys342 of the DA transporter (DAT); Cys254 of vesicular H+-ATPase [1-4]. In addition, the DA quinones will deplete glutathione (GSH) and damage mitochondria thereby causing secondary oxidative stress. Subsequent membrane lipid peroxidation can generate a family of unsaturated aldehyde derivatives that includes 4- hydroxy-2-nonenal (HNE), 4-oxy-2-nonenal (ONE) and acrolein. These are also highly reactive soft electrophiles that rapidly form Michael-type adducts with soft nucleophilic cysteine thiolate groups on nerve terminal proteins [5,6]. Thus, a theoretical PD neuropathogenesis involving impaired storage and subsequently elevated cytosolic DA levels could initiate an electrophile cascade. However, rather than targeting a single protein (e.g., VMAT2), the electrophile mixture would inhibit the function of diverse thiolate-directed proteins that constitute an electrophile- responsive nerve terminal proteome [1].

    Indeed, kinetic and proteomic analyses have revealed that exposure to soft electrophiles (e.g., HNE, acrolein, acrylamide) impaired DA uptake, release and vesicular storage by forming thiolate adducts with the proteins that mediate these presynaptic processes; i.e., DAT, NSF and VMAT2 [7,8]. As the results of the Pifl study imply, the proposed electrophile cascade could be initiated by VMAT2 inhibition through direct interaction with, for example, endogenous inhibitory proteins (e.g., a-synuclein) or environmental toxicants (e.g., organochlorine insecticides). With respect to the latter possibility, it is noteworthy that acrolein, methylvinyl ketone and other unsaturated aldehyde and carbonyl derivatives are significant environmental and dietary pollutants. As discussed above, these chemicals are soft electrophiles that produce toxicity through a common mechanism; thiolate adduct formation. Thus, it is possible that these environmental toxicants interact with endogenous soft electrophiles and thereby accelerate the development of PD and other neurodegenerative conditions [2,3,9,10].

    References

    1.LoPachin RM, Barber DS. Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants. Toxicol Sci 2006; 94:240-255.

    2.LoPachin RM, Gavin T. Molecular Mechanism of Acrylamide Neurotoxicity: Lessons Learned from Organic Chemistry. Environ Health Persp 2012; 120: 1650-1657.

    3.LoPachin RM, Gavin T. Mechanisms of Aldehyde Toxicity: A Chemical Perspective. Chem. Res. Toxicol. 2014; Doi.org/10.1021/tx5001046.

    4.LoPachin RM, Gavin T, DeCaprio AP, Barber DS. Application of the Hard and Soft, Acids and Bases Theory to Toxicant-Target Interactions. Chem. Res. Toxicol. 2012; 25: 239-251.

    5.LoPachin RM, Gavin T, Petersen DR, Barber DS. Molecular Mechanisms of 4- Hydroxy-2-nonenal and Acrolein: Nucleophilic Targets and Adduct Formation. Chem. Res. Toxicol. 2009; 22: 1499-1508.

    6.Martyniuk CJ, Fang B, Koomen JM, Gavin T, LoPachin RM, Barber DS. Molecular Mechanism of Glyceraldehyde-3-Phosphate Dehydrogenase Inactivation by alpha,beta-Unsaturated Carbonyl Derivatives. Chem. Res. Toxicol. 2011; 24: 2302-2311.

    7.Barber DS, Stevens S, LoPachin RM. Proteomic Analyses of Rat Striatal Synaptosomes During Acrylamide Intoxication at a Low Dose-Rate. Toxicol. Sci. 2007; 100: 156-167.

    8.LoPachin RM, He D, Soma D. Acrylamide Inhibits Dopamine Uptake in Rat Striatal Synaptic Vesicles. Toxicol. Sci. 2006; 89: 224-234.

    9.LoPachin RM, Gavin T, Barber DS. Molecular Mechanisms of the Conjugated alpha,beta-unsaturated Carbonyl Derivatives: Relevance to Neurotoxicity and Neurodegenerative Diseases. Toxicol. Sci. 2008; 104: 235-249.

    10.LoPachin RM, Barber DS, Gavin T. Type-2 Alkenes Mediate Synaptoxicity in Neurodegenerative Diseases. NeuroToxicology. 2008; 29: 871-882.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
  • Published on: (7 July 2014)
    Page navigation anchor for Re:Vesicular Storage Defect
    Re:Vesicular Storage Defect
    • Christian Pifl
    • Other Contributors:
      • Oleh Hornykiewicz

    We thank Dr. Burke and Dr. Goldstein for their insightful comments. We agree that Dr. Burke's group has very convincingly shown that DOPAL might be the agent which induces degeneration of dopaminergic neurons if excessively produced within them, and that the neurochemical findings on catechol metabolite patterns in post-mortem striatal PD tissue obtained in ingenious experiments by Dr. Goldstein's group pointed to a vesic...

    Show More

    We thank Dr. Burke and Dr. Goldstein for their insightful comments. We agree that Dr. Burke's group has very convincingly shown that DOPAL might be the agent which induces degeneration of dopaminergic neurons if excessively produced within them, and that the neurochemical findings on catechol metabolite patterns in post-mortem striatal PD tissue obtained in ingenious experiments by Dr. Goldstein's group pointed to a vesicular storage defect (as also mentioned in our article). Since we propose that the VMAT2 defect may be the primary abnormality with increased cytosolic dopamine metabolism by MAO being one of possible sequels, the challenge right now is to find the molecular basis as an explanation for this primary event.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
  • Published on: (6 July 2014)
    Page navigation anchor for DOPAL toxicity explains how vesicular dopamine defect leads to Parkinson disease
    DOPAL toxicity explains how vesicular dopamine defect leads to Parkinson disease
    • William J Burke, Neurologist

    The simplest explanation for Pifl's results is that increased cytosolic dopamine (DA) levels, resulting from defective DA storage, produces an increase in the DA toxic metabolite, 3,4 dihydroxyphenylacetaldehyde (DOPAL).

    Recent scientific investigations provide mounting evidence for a key role for DOPAL, the monoamine oxidase metabolite (MAO) of DA, in the pathogenesis of Parkinson disease (PD) and in its motor...

    Show More

    The simplest explanation for Pifl's results is that increased cytosolic dopamine (DA) levels, resulting from defective DA storage, produces an increase in the DA toxic metabolite, 3,4 dihydroxyphenylacetaldehyde (DOPAL).

    Recent scientific investigations provide mounting evidence for a key role for DOPAL, the monoamine oxidase metabolite (MAO) of DA, in the pathogenesis of Parkinson disease (PD) and in its motor symptoms. DOPAL disrupts mitochondrial function and kills DA neurons in vitro (Kristal et al., 2001) and in vivo (Burke et al., 2003). There are several animal models of PD which depend on DOPAL toxicity (Betarbet et al., 2000; Panneton et al., 2012; Wey et al., 2012). DOPAL, when injected into the SN, produces an animal model of PD (Panneton et al., 2012). Genetic (Wey et al. 2012) or environmental (Betarbet et al., 2000) manipulations which increase DOPAL levels (Lamensdorf et al., 2000) in DA neurons kill the DA neurons and provide pathological and behavioral models of PD (Panneton et al., 2012; Wey et al., 2012.

    References:

    Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV ,Greenamyre JT. Chronic systemic pesticide exposure reproduces feature of Parkinson's disease. Nature, Neuroscience 2000;3:1301-1306.

    Burke WJ. 3,4-Dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease. Current Drug Targets. CNS & Neurological Disorders 2003;2:143-148.

    Fitzmaurice AG, Rhodes SL, Cockburn M, Ritz B ,Bronstein JM. Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease. Neurology 2014;82:419-426.

    Goldstein DS, Sullivan P, Holmes C, Kopin IJ, Basile MJ ,Mash DC. Catechols in post-mortem brain of patients with Parkinson disease. Eur.J.Neurol. 2011;18:703-710.

    Goldstein DS, Sullivan P, Holmes C, Miller GW, Alter S, Strong R, Mash DC, Kopin IJ, Sharabi Y. Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease. J.Neurochem. 2013;126:591-603.

    Kristal BS, Conway AD, Brown AM, Jain JC, Ulluci PA, Li SW ,Burke WJ. Selective dopaminergic vulnerability: 3,4-dihydroxyphenylacetaldehyde targets mitochondria. Free Radic.Biol.Med. 2001;30:24-931.

    Lamensdorf I, Eisenhofer G, Harvey-White J, Hayakawa Y, Kirk K ,Kopin IJ. Metabolic stress in PC12 cells induces the formation of the endogenous dopaminergic neurotoxin, 3,4-dihydroxyphenylacetaldehyde. J.Neurosci.Res. 2000;60:552-558.

    Panneton WM, Kumar V, Gan Qi, Burke WJ ,Galvin JE. The neuroxicity of DOPAL: Behaviroral and stereological evidence for its role in Parkinson's pathogenesis. PloS One 2012;5:e15251-

    Wey MC, Fernandez E, Martinez PA, Sullivan P, Goldstein DS ,Strong R. Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson's disease. PLoS.One. 2012;7:e31522-

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
  • Published on: (27 June 2014)
    Page navigation anchor for Vesicular Storage Defect
    Vesicular Storage Defect
    • David S. Goldstein, Chief, Clinical Neurocardiology Section, CNP/DIR

    The study reported by Pifl et al. provides important confirmation of our post-mortem neurochemical data (Goldstein et al., 2013) indicating a vesicular storage defect in Parkinson's disease (PD). PD is associated with profound loss of myocardial noradrenergic innervation, and we have obtained in vivo and post-mortem neurochemical evidence for a similar abnormality of vesicular sequestration contributing to the myocardial nore...

    Show More

    The study reported by Pifl et al. provides important confirmation of our post-mortem neurochemical data (Goldstein et al., 2013) indicating a vesicular storage defect in Parkinson's disease (PD). PD is associated with profound loss of myocardial noradrenergic innervation, and we have obtained in vivo and post-mortem neurochemical evidence for a similar abnormality of vesicular sequestration contributing to the myocardial norepinephrine depletion attending PD (Goldstein et al., 2011; Goldstein et al., 2014). Taken together, our results and those reported by Pifl et al. provide an explanation for the profound catecholamine deficiency first reported by Hornykiewicz and colleagues more than a half century ago (Ehringer and Hornykiewicz, 1960). Considering that Dr. Hornykiewicz is the senior author of the present study, the article has substantial historic significance.

    REFERENCES

    Ehringer H, Hornykiewicz O (1960) [Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system.]. Wien Klin Wochenschr 38:1236-1239.

    Goldstein DS, Holmes C, Kopin IJ, Sharabi Y (2011) Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases. J Clin Inv 121:3320-3330.

    Goldstein DS, Sullivan P, Holmes C, Miller GW, Sharabi Y, Kopin IJ (2014) A vesicular sequestration to oxidative deamination shift in myocardial sympathetic nerves in Parkinson's disease. J Neurochem. doi: 10.1111/jnc.12766. [Epub ahead of print]

    Goldstein DS, Sullivan P, Holmes C, Miller GW, Alter S, Strong R, Mash DC, Kopin IJ, Sharabi Y (2013) Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease. J Neurochem 126:591-603.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.

Related Articles

Cited By...

More in this TOC Section

Articles

  • Choice Behavior Guided by Learned, But Not Innate, Taste Aversion Recruits the Orbitofrontal Cortex
  • Maturation of Spontaneous Firing Properties after Hearing Onset in Rat Auditory Nerve Fibers: Spontaneous Rates, Refractoriness, and Interfiber Correlations
  • Insulin Treatment Prevents Neuroinflammation and Neuronal Injury with Restored Neurobehavioral Function in Models of HIV/AIDS Neurodegeneration
Show more Articles

Neurobiology of Disease

  • The role of retinal dopamine D1 receptors in ocular growth and myopia development in mice
  • ALS-associated KIF5A mutation causes locomotor deficits associated with cytoplasmic inclusions, alterations of neuromuscular junctions and motor neuron loss
  • Perturbed Information Processing Complexity in Experimental Epilepsy
Show more Neurobiology of Disease
  • Home
  • Alerts
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Policy
  • Contact
(JNeurosci logo)
(SfN logo)

Copyright © 2023 by the Society for Neuroscience.
JNeurosci Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.