title: Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions.
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.
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Elstner
authors.forename: Sarina K
authors.initials: SK
authors.lastname: Müller
authors.forename: Lars
authors.initials: L
authors.lastname: Leidolt
authors.forename: Christoph
authors.initials: C
authors.lastname: Laub
authors.forename: Lena
authors.initials: L
authors.lastname: Krieg
authors.forename: Falk
authors.initials: F
authors.lastname: Schlaudraff
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.forename: Chris
authors.initials: C
authors.lastname: Morris
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
mesh_terms: D059331:Adrenergic Neurons / Q000166:cytology / Q000502:physiology*; D000368:Aged; D000369:Aged, 80 and over; D001933:Brain Stem / Q000033:anatomy & histology* / Q000378:metabolism / Q000473:pathology; D059329:Cholinergic Neurons / Q000166:cytology / Q000502:physiology*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000502:physiology*; D017353:Gene Deletion; D006801:Humans; D008543:Melanins / Q000378:metabolism*; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D008543:Melanins; D018377:Neurotransmitter Agents; C014121:neuromelanin