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Neuromelanin, Neurotransmitter Status and Brainstem Location Determine the Differential Vulnerability of Catecholaminergic Neurons to Mitochondrial DNA Deletions

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Neuromelanin, Neurotransmitter Status and Brainstem Location Determine the Differential Vulnerability of Catecholaminergic Neurons to Mitochondrial DNA Deletions UC San Diego UC San Diego Previously Published Works Title Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions Permalink https://escholarship.org/uc/item/8jz0f449 Journal Molecular Brain, 4(1) ISSN 1756-6606 Authors Elstner, Matthias Müller, Sarina K Leidolt, Lars et al. Publication Date 2011-12-21 DOI http://dx.doi.org/10.1186/1756-6606-4-43 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Elstner et al. Molecular Brain 2011, 4:43 http://www.molecularbrain.com/content/4/1/43 SHORTREPORT Open Access Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions Matthias Elstner1,2, Sarina K Müller1, Lars Leidolt1, Christoph Laub1,2, Lena Krieg1, Falk Schlaudraff3, Birgit Liss3, Chris Morris4,5, Douglass M Turnbull4,6, Eliezer Masliah7, Holger Prokisch8,9, Thomas Klopstock1,2† and Andreas Bender1,10*† Abstract Background: Deletions of the mitochondrial DNA (mtDNA) accumulate to high levels in dopaminergic neurons of the substantia nigra pars compacta (SNc) in normal aging and in patients with Parkinson’s disease (PD). Human nigral neurons characteristically contain the pigment neuromelanin (NM), which is believed to alter the cellular redox-status. The impact of neuronal pigmentation, neurotransmitter status and brainstem location on the susceptibility to mtDNA damage remains unclear. We quantified mtDNA deletions (ΔmtDNA) in single pigmented and non-pigmented catecholaminergic, as well as non-catecholaminergic neurons of the human SNc, the ventral tegmental area (VTA) and the locus coeruleus (LC), using laser capture microdissection and single-cell real-time PCR. Results: In healthy aged individuals, ΔmtDNA levels were highest in pigmented catecholaminergic neurons (25.2 ± 14.9%), followed by non-pigmented catecholamergic (18.0 ± 11.2%) and non-catecholaminergic neurons (12.3 ± 12.3%; p < 0.001). Within the catecholaminergic population, ΔmtDNA levels were highest in dopaminergic neurons of the SNc (33.9 ± 21.6%) followed by dopaminergic neurons of the VTA (21.9 ± 12.3%) and noradrenergic neurons of the LC (11.1 ± 11.4%; p < 0.001). In PD patients, there was a trend to an elevated mutation load in surviving non-pigmented nigral neurons (27.13 ± 16.73) compared to age-matched controls (19.15 ± 11.06; p = 0.052), but levels where similar in pigmented nigral neurons of PD patients (41.62 ± 19.61) and controls (41.80 ± 22.62). Conclusions: Catecholaminergic brainstem neurons are differentially susceptible to mtDNA damage. Pigmented dopaminergic neurons of the SNc show the highest ΔmtDNA levels, possibly explaining the exceptional vulnerability of the nigro-striatal system in PD and aging. Although loss of pigmented noradrenergic LC neurons also is an early feature of PD pathology, mtDNA levels are not elevated in this nucleus in healthy controls. Thus, ΔmtDNA are neither an inevitable consequence of catecholamine metabolism nor a universal explanation for the regional vulnerability seen in PD. Keywords: Parkinson disease, aging, neurodegeneration, catecholaminergic neurons, mitochondrial DNA, single neuron analysis, laser-microdissection * Correspondence: [email protected] † Contributed equally 1Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians- University, 81377 Munich, Germany Full list of author information is available at the end of the article © 2011 Elstner et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Elstner et al. Molecular Brain 2011, 4:43 Page 2 of 10 http://www.molecularbrain.com/content/4/1/43 Background [19]. Thus, increased ROS generation, mtDNA mutations Oxidative stress and mitochondrial dysfunction are and mitochondrial dysfunction might pave the way for believed to have a dominant role in mechanisms of aging neurodegenerative processes in PD [20]. and neurodegenerative disorders such as Parkinson disease In this context the question arises, if location, neuro- (PD) [1]. The mitochondrial theory of aging proposes that transmitter status or the presence of NM determines the production of reactive oxygen species (ROS) in mitochon- vulnerability of dopaminergic nigral neurons to accumu- dria causes accumulating damage to proteins, lipids, and late mtDNA damage. Herein, we investigated the associa- mitochondrial DNA (mtDNA). As a consequence, mito- tion of these factors with mtDNA levels in single post chondrial dysfunction and ROS production may build up mortem catecholaminergic neurons that were dissected in a vicious cycle that eventually results in cell death [2,3]. from the SNc, the ventral tegmental area (VTA) and the Damage to mtDNA is central to this theory and early stu- locus coeruleus (LC) of post mortem brains of healthy dies provide evidence for the accumulation of somatic aged individuals and PD patients. mtDNA deletions (ΔmtDNA) in aging postmitotic tissues with high energy demand, such as skeletal muscle and the Results brain [4,5]. Nevertheless, due to the low abundance of Association of pigmentation and ΔmtDNA levels ΔmtDNA detected in crude tissue homogenates, their In the adult human brain, NM is easily identifiable as a functional significance remained controversial. By combin- black-brown pigment by light microscopy. NM-containing ing laser-microdissection (LMD) with a quantitative real- neurons are distributed throughout the entire brainstem, time PCR (RT-PCR) assay, we demonstrated the age- but the largest clusters are found in the SNc, the VTA and related accumulation of clonally expanded ΔmtDNA the LC [18]. In a pilot experiment, we randomly collected in individual post mortem dopaminergic neurons of the pigmented neurons from the SNc of five healthy controls substantia nigra pars compacta (SNc) [6]. Indicative of (80.8 ± 8.6 y) and compared ΔmtDNA levels to those seen a resulting functionally relevant biochemical defect, neu- in non-pigmented neurons within the same specimens. rons with high levels (~ 60%) ΔmtDNA had mitochondrial We found that non-pigmented neurons had a mean of cytochrome-c oxidase (COX, complex IV of the mitochon- 31.0 ± 25.1% ΔmtDNA, whereas pigmented neurons had a drial respiratoy chain) deficiency on histochemical exami- mean of 49.2% ± 18.3% ΔmtDNA (p = 0.017). This preli- nation in PD patients and controls. These findings were minary data suggested that an increased vulnerability is independently confirmed using a different methodological associated with NM-pigmentation of midbrain neurons in approach [7]. Our studies into the regional distribution of healthy aged controls. ΔmtDNA further showed that dopaminergic nigral neu- Encouraged by these results, we next established an rons have a higher propensity to accumulate ΔmtDNA immunohistochemical staining protocol to facilitate a than extranigral populations, e.g. in the putamen, the hip- more specific and extensive analysis of catecholaminergic pocampus or the frontal cortex [8,9]. Besides their cate- neurons of the SNc, the VTA and the LC. Using a succes- cholaminergic neurotransmitter status, a prominent sive TH/NeuN antibody labeling and DAB/HRP reaction, feature of these neurons is their pigmentation, i.e. the catecholaminergic (TH+) neurons were positively discrimi- intraneuronal accumulation of neuromelanin (NM). NM nated from non-catecholaminergic (TH-)neurons(e.g. has long been considered a cellular waste product via the GABAergic interneurons) and from glia cells. TH+ immu- non-enzymatic oxidization of dopamine or other catecho- noreactivity results in a brown cytosolic reaction product, lamines, but some evidence points towards a regulated while TH- neurons remain unstained. NeuN immunoreac- production that might involve alpha-synuclein [10,11]. Its tivity results in a grey appearance of TH- neurons due to contribution to neurodegenerative processes is far from the successive DAB/Nickel reaction. Pigmented and non- understood as there is evidence for both neuroprotective pigmented neurons were further distinguished by the and neurotoxic properties [12-14]. As a possible mechan- visiblepresenceorabsenceofNM(Figure1).Forthese ism, it has been proposed that NM might serve to control studies, we extended the analysis with an independent iron homeostasis within pigmented neurons [15]. If the group of 19 controls (68.8 ± 19.4 y) and 14 PD specimens iron chelation ability of NM is reduced, increased levels of (75.1 ± 7.8 y). intra-neuronal free iron may stimulate ROS production. In We first asked, whether our initial data could be vali- PD, pigmented neurons contain less NM than in healthy dated after immunhistochemical identification of cate- brains, while the optical density of the pigment is cholaminergic neurons. To this end, we analyzed increased [16,17]. These changes of neuronal NM content ΔmtDNA levels of TH+ neurons captured from all three and composition may cause a loss of protective properties regions (SN, VTA and LC). In a combined analysis of [18]. Indeed, we have previously shown that individual all regions, we confirmed a significant difference of dopaminergic neurons have elevated iron levels in PD mtDNA levels between non-pigmented (18.0%
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