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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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Levels of mitochondrial DNA deletions in nigral neurons of PD and controls. Pigmented neurons (TH+/NM+) of the SNc have considerably higher ΔmtDNA levels than non-pigmented neurons (TH+/NM-) in controls (C) and PD (*** p = 0.001). In nonpigmented neurons there was a trend to higher deletions in PD vs. controls (p = 0.052).
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Figure 4: Levels of mitochondrial DNA deletions in nigral neurons of PD and controls. Pigmented neurons (TH+/NM+) of the SNc have considerably higher ΔmtDNA levels than non-pigmented neurons (TH+/NM-) in controls (C) and PD (*** p = 0.001). In nonpigmented neurons there was a trend to higher deletions in PD vs. controls (p = 0.052).

Mentions: Lastly, we quantified ΔmtDNA levels in PD cases (n = 14; mean age 75.1 ± 7.8 years). Collection and analysis was restricted to SN dopaminergic neurons due to the paucity of suitable tissue samples. In PD, ΔmtDNA levels of pigmented neurons (41.62 ± 19.61) were again higher than those of non-pigmented neurons (27.13 ± 16.73; p = 9.6E-05), thus independently reproducing the results seen in the control group. We then compared ΔmtDNA levels in PD cases to those seen in age-matched controls (n = 19; mean age 78.7 ± 9.0 years). In non-pigmented neurons there was a trend to higher deletions in PD vs. controls (PD = 27.13 ± 16.73; controls = 19.15 ± 11.06; p = 0.052). No difference was seen for pigmented neurons in PD (41.62 ± 19.61) and controls (41.80 ± 22.62; Figure 4).


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)

Levels of mitochondrial DNA deletions in nigral neurons of PD and controls. Pigmented neurons (TH+/NM+) of the SNc have considerably higher ΔmtDNA levels than non-pigmented neurons (TH+/NM-) in controls (C) and PD (*** p = 0.001). In nonpigmented neurons there was a trend to higher deletions in PD vs. controls (p = 0.052).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Levels of mitochondrial DNA deletions in nigral neurons of PD and controls. Pigmented neurons (TH+/NM+) of the SNc have considerably higher ΔmtDNA levels than non-pigmented neurons (TH+/NM-) in controls (C) and PD (*** p = 0.001). In nonpigmented neurons there was a trend to higher deletions in PD vs. controls (p = 0.052).
Mentions: Lastly, we quantified ΔmtDNA levels in PD cases (n = 14; mean age 75.1 ± 7.8 years). Collection and analysis was restricted to SN dopaminergic neurons due to the paucity of suitable tissue samples. In PD, ΔmtDNA levels of pigmented neurons (41.62 ± 19.61) were again higher than those of non-pigmented neurons (27.13 ± 16.73; p = 9.6E-05), thus independently reproducing the results seen in the control group. We then compared ΔmtDNA levels in PD cases to those seen in age-matched controls (n = 19; mean age 78.7 ± 9.0 years). In non-pigmented neurons there was a trend to higher deletions in PD vs. controls (PD = 27.13 ± 16.73; controls = 19.15 ± 11.06; p = 0.052). No difference was seen for pigmented neurons in PD (41.62 ± 19.61) and controls (41.80 ± 22.62; Figure 4).

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