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Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions.

Elstner M, Müller SK, Leidolt L, Laub C, Krieg L, Schlaudraff F, Liss B, Morris C, Turnbull DM, Masliah E, Prokisch H, Klopstock T, Bender A - Mol Brain (2011)

Bottom Line: 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).Catecholaminergic brainstem neurons are differentially susceptible to mtDNA damage.Thus, ΔmtDNA are neither an inevitable consequence of catecholamine metabolism nor a universal explanation for the regional vulnerability seen in PD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University, 81377 Munich, Germany.

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.

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Differential vulnerability of catecholaminergic brainstem neurons in healthy aged controls. 3-D model of the brain showing location of brainstem nuclei and ΔmtDNA levels of pigmented (TH+/NM+) and non-pigmented (TH+/NM-) catecholaminergic neurons, as well as non-catecholaminergic (TH-) neurons in these nuclei. Values represent mean ± standard deviation of data collected from healthy aged controls (78.7 ± 9.0 years). Highest deletion levels are seen in pigmented neurons of the SNc (black). VTA neurons show intermediate ΔmtDNA levels (grey) and LC neurons lowest (light grey). PD pathology is deviating from this pattern, as SNc and LC show heavy degeneration whereas the VTA is relatively spared.
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Figure 5: Differential vulnerability of catecholaminergic brainstem neurons in healthy aged controls. 3-D model of the brain showing location of brainstem nuclei and ΔmtDNA levels of pigmented (TH+/NM+) and non-pigmented (TH+/NM-) catecholaminergic neurons, as well as non-catecholaminergic (TH-) neurons in these nuclei. Values represent mean ± standard deviation of data collected from healthy aged controls (78.7 ± 9.0 years). Highest deletion levels are seen in pigmented neurons of the SNc (black). VTA neurons show intermediate ΔmtDNA levels (grey) and LC neurons lowest (light grey). PD pathology is deviating from this pattern, as SNc and LC show heavy degeneration whereas the VTA is relatively spared.

Mentions: To generate a concise picture of ΔmtDNA levels in the aged human brain, we extracted data coming from all control individuals over 60 years of age (n = 19; mean age 78.7 ± 9.0 years). In our synopsis, individual levels of ΔmtDNA in relation to brainstem location, pigmentation and neurotransmitter status are illustrated (Figure 5). This data underlines the prominent vulnerability of pigmented nigral neurons, followed by pigmented neurons of the VTA and non-pigmented neurons of both nuclei, whereas the LC has overall low deletion levels.


Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions.

Elstner M, Müller SK, Leidolt L, Laub C, Krieg L, Schlaudraff F, Liss B, Morris C, Turnbull DM, Masliah E, Prokisch H, Klopstock T, Bender A - Mol Brain (2011)

Differential vulnerability of catecholaminergic brainstem neurons in healthy aged controls. 3-D model of the brain showing location of brainstem nuclei and ΔmtDNA levels of pigmented (TH+/NM+) and non-pigmented (TH+/NM-) catecholaminergic neurons, as well as non-catecholaminergic (TH-) neurons in these nuclei. Values represent mean ± standard deviation of data collected from healthy aged controls (78.7 ± 9.0 years). Highest deletion levels are seen in pigmented neurons of the SNc (black). VTA neurons show intermediate ΔmtDNA levels (grey) and LC neurons lowest (light grey). PD pathology is deviating from this pattern, as SNc and LC show heavy degeneration whereas the VTA is relatively spared.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3278372&req=5

Figure 5: Differential vulnerability of catecholaminergic brainstem neurons in healthy aged controls. 3-D model of the brain showing location of brainstem nuclei and ΔmtDNA levels of pigmented (TH+/NM+) and non-pigmented (TH+/NM-) catecholaminergic neurons, as well as non-catecholaminergic (TH-) neurons in these nuclei. Values represent mean ± standard deviation of data collected from healthy aged controls (78.7 ± 9.0 years). Highest deletion levels are seen in pigmented neurons of the SNc (black). VTA neurons show intermediate ΔmtDNA levels (grey) and LC neurons lowest (light grey). PD pathology is deviating from this pattern, as SNc and LC show heavy degeneration whereas the VTA is relatively spared.
Mentions: To generate a concise picture of ΔmtDNA levels in the aged human brain, we extracted data coming from all control individuals over 60 years of age (n = 19; mean age 78.7 ± 9.0 years). In our synopsis, individual levels of ΔmtDNA in relation to brainstem location, pigmentation and neurotransmitter status are illustrated (Figure 5). This data underlines the prominent vulnerability of pigmented nigral neurons, followed by pigmented neurons of the VTA and non-pigmented neurons of both nuclei, whereas the LC has overall low deletion levels.

Bottom Line: 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).Catecholaminergic brainstem neurons are differentially susceptible to mtDNA damage.Thus, ΔmtDNA are neither an inevitable consequence of catecholamine metabolism nor a universal explanation for the regional vulnerability seen in PD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University, 81377 Munich, Germany.

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.

Show MeSH
Related in: MedlinePlus