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      Living on the edge with too many mouths to feed: Why dopamine neurons die

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          Abstract

          Although genes, protein aggregates, environmental toxins, and other factors associated with Parkinson’s disease (PD) are widely distributed in the nervous system and affect many classes of neurons, a consistent feature of PD is the exceptional and selective vulnerability of dopamine (DA) neurons of the SNc. What is it about these neurons, among all other neurons in the brain, that makes them so susceptible in PD? We hypothesize that a major contributory factor is the unique cellular architecture of SNc DA neuron axons. Their large, complex axonal arbour puts them under such a tight energy budget that it makes them particularly susceptible to factors that contribute to cell death, including unique molecular characteristics associated with SNc DA neurons and nonspecific, nervous-system–wide factors. © 2012 Movement Disorder Society

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          Stages in the development of Parkinson's disease-related pathology.

          Heiko Braak, Estifanos Ghebremedhin, Udo Rüb … (2004)
          The synucleinopathy, idiopathic Parkinson's disease, is a multisystem disorder that involves only a few predisposed nerve cell types in specific regions of the human nervous system. The intracerebral formation of abnormal proteinaceous Lewy bodies and Lewy neurites begins at defined induction sites and advances in a topographically predictable sequence. As the disease progresses, components of the autonomic, limbic, and somatomotor systems become particularly badly damaged. During presymptomatic stages 1-2, inclusion body pathology is confined to the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus. In stages 3-4, the substantia nigra and other nuclear grays of the midbrain and forebrain become the focus of initially slight and, then, severe pathological changes. At this point, most individuals probably cross the threshold to the symptomatic phase of the illness. In the end-stages 5-6, the process enters the mature neocortex, and the disease manifests itself in all of its clinical dimensions.
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            The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease.

            P Damier, E Hirsch, Y Agid … (1999)
            To achieve accuracy in studying the patterns of loss of midbrain dopamine-containing neurons in Parkinson's disease, we used compartmental patterns of calbindin D(28K) immunostaining to subdivide the substantia nigra with landmarks independent of the degenerative process. Within the substantia nigra pars compacta, we identified dopamine-containing neurons in the calbindin-rich regions ('matrix') and in five calbindin-poor pockets ('nigrosomes') defined by analysis of the three-dimensional networks formed by the calbindin-poor zones. These zones were recognizable in all of the brains, despite severe loss of dopamine-containing neurons. The degree of loss of dopamine-containing neurons in the substantia nigra pars compacta was related to the duration of the disease, and the cell loss followed a strict order. The degree of neuronal loss was significantly higher in the nigrosomes than in the matrix. Depletion was maximum (98%) in the main pocket (nigrosome 1), located in the caudal and mediolateral part of the substantia nigra pars compacta. Progressively less cell loss was detectable in more medial and more rostral nigrosomes, following the stereotyped order of nigrosome 1 > nigrosome 2 > nigrosome 4 > nigrosome 3 > nigrosome 5. A parallel, but lesser, caudorostral gradient of cell loss was observed for dopamine-containing neurons included in the matrix. This pattern of neuronal loss was consistent from one parkinsonian substantia nigra pars compacta to another. The spatiotemporal progression of neuronal loss related to disease duration can thus be drawn in the substantia nigra pars compacta for each Parkinson's disease patient: depletion begins in the main pocket (nigrosome 1) and then spreads to other nigrosomes and the matrix along rostral, medial and dorsal axes of progression.
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              Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system.

              Stephan Lammel, Andrea Hetzel, Olga Häckel … (2008)
              The mesocorticolimbic dopamine system is essential for cognitive and emotive brain functions and is thus an important target in major brain diseases like schizophrenia, drug addiction, and attention deficit hyperactivity disorder. However, the cellular basis for the diversity in behavioral functions and associated dopamine-release pattern within the mesocorticolimbic system has remained unclear. Here, we report the identification of a type of dopaminergic neuron within the mesocorticolimbic dopamine system with unconventional fast-firing properties and small DAT/TH mRNA expression ratios that selectively projects to prefrontal cortex and nucleus accumbens core and medial shell as well as to basolateral amygdala. In contrast, well-described conventional slow-firing dopamine midbrain neurons only project to the lateral shell of the nucleus accumbens and the dorsolateral striatum. Among this dual dopamine midbrain system defined in this study by converging anatomical, electrophysiological, and molecular properties, mesoprefrontal dopaminergic neurons are unique, as only they do not possess functional somatodendritic Girk2-coupled dopamine D2 autoreceptors.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mov Disord
                Journal ID (iso-abbrev): Mov. Disord
                Journal ID (publisher-id): mds
                Title: Movement Disorders
                Publisher: Wiley Subscription Services, Inc., A Wiley Company (Hoboken )
                ISSN (Print): 0885-3185
                ISSN (Electronic): 1531-8257
                Publication date (Print): September 2012
                Publication date (Electronic): October 2012
                Volume: 27
                Issue: 12
                Pages: 1478-1483
                Affiliations
                [1 ]Medical Research Council Anatomical Neuropharmacology Unit, Department of Pharmacology, and Oxford Parkinson’s Disease Centre, University of Oxford, Oxford, UK
                [2 ]Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece
                Author notes
                *Dr. J. Paul Bolam, MRC Anatomical Neuropharmacology Unit, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3TH, United Kingdom; paul.bolam@ 123456pharm.ox.ac.uk

                Funding agencies: The authors’ own work described in this article was supported by the Medical Research Council, UK (grant no.: U138164490), Parkinson’s UK (grant nos.: G-0601 and K-1103), and the European Community (FP7: HEALTH-F2-2008-201716).

                Relevant conflicts of interest/financial disclosures: Nothing to report.

                Full financial disclosures and author roles may be found in the online version of this article.

                Article
                DOI: 10.1002/mds.25135
                PMC ID: 3504389
                PubMed ID: 23008164
                SO-VID: d8cf9684-521f-4dc7-af0f-6e83250362c7
                Copyright © Copyright © 2012 Movement Disorder Society
                License:

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                Date received : 24 April 2012
                Date revision received : 2 July 2012
                Date accepted : 17 July 2012
                Categories
                Subject: Viewpoints

                ScienceOpen disciplines: Medicine
                Keywords: parkinson’s,neurodegeneration,energy,dopamine neurons
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: parkinson’s, neurodegeneration, energy, dopamine neurons

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