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Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease.

ABSTRACT: Dopamine-releasing neurons within the Substantia nigra (SN DA) are particularly vulnerable to degeneration compared to other dopaminergic neurons. The age-dependent, progressive loss of these neurons is a pathological hallmark of Parkinson's disease (PD), as the resulting loss of striatal dopamine causes its major movement-related symptoms. SN DA neurons release dopamine from their axonal terminals within the dorsal striatum, and also from their cell bodies and dendrites within the midbrain in a calcium- and activity-dependent manner. Their intrinsically generated and metabolically challenging activity is created and modulated by the orchestrated function of different ion channels and dopamine D2-autoreceptors. Here, we review increasing evidence that the mechanisms that control activity patterns and calcium homeostasis of SN DA neurons are not only crucial for their dopamine release within a physiological range but also modulate their mitochondrial and lysosomal activity, their metabolic stress levels, and their vulnerability to degeneration in PD. Indeed, impaired calcium homeostasis, lysosomal and mitochondrial dysfunction, and metabolic stress in SN DA neurons represent central converging trigger factors for idiopathic and familial PD. We summarize double-edged roles of ion channels, activity patterns, calcium homeostasis, and related feedback/feed-forward signaling mechanisms in SN DA neurons for maintaining and modulating their physiological function, but also for contributing to their vulnerability in PD-paradigms. We focus on the emerging roles of maintained neuronal activity and calcium homeostasis within a physiological bandwidth, and its modulation by PD-triggers, as well as on bidirectional functions of voltage-gated L-type calcium channels and metabolically gated ATP-sensitive potassium (K-ATP) channels, and their probable interplay in health and PD. We propose that SN DA neurons possess several feedback and feed-forward mechanisms to protect and adapt their activity-pattern and calcium-homeostasis within a physiological bandwidth, and that PD-trigger factors can narrow this bandwidth. We summarize roles of ion channels in this view, and findings documenting that both, reduced as well as elevated activity and associated calcium-levels can trigger SN DA degeneration. This article is part of a special issue on Parkinson disease.

SUBMITTER: Duda J

PROVIDER: S-EPMC5095868 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease.

Duda Johanna J Pötschke Christina C Liss Birgit B

Journal of neurochemistry 20160323

Dopamine-releasing neurons within the Substantia nigra (SN DA) are particularly vulnerable to degeneration compared to other dopaminergic neurons. The age-dependent, progressive loss of these neurons is a pathological hallmark of Parkinson's disease (PD), as the resulting loss of striatal dopamine causes its major movement-related symptoms. SN DA neurons release dopamine from their axonal terminals within the dorsal striatum, and also from their cell bodies and dendrites within the midbrain in a ...[more]

PMID: 26865375

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Project description:BACKGROUND:Susceptibility MRI may capture Parkinson's disease-related pathology. This study delineated longitudinal changes in different substantia nigra regions. METHODS:Seventy-two PD patients and 62 controls were studied at both baseline and after 18 months with MRI. R2* and quantitative susceptibility mapping values from the substantia nigra pars compacta and substantia nigra pars reticulata were calculated. Mixed-effects models compared controls with PD or PD subgroups having different disease durations: early (<1 year), middle (<5 years, middle-stage PD), and late (>5 years, late-stage PD). Pearson's correlation assessed associations between imaging and clinical measures. RESULTS:At baseline, R2* and quantitative susceptibility mapping were higher in both the substantia nigra pars compacta and substantia nigra pars reticulata in all PD patients (group effect, P???0.003). Longitudinally, the substantia nigra pars compacta R2* showed a faster increase in PD compared with controls (time?×?group, P?=?0.002), whereas quantitative susceptibility mapping did not (P?=?0.668). The substantia nigra pars reticulata R2* and quantitative susceptibility mapping did not differ between PD and controls (time?×?group, P???0.084), although both decreased longitudinally (time effect, P???0.004). Baseline substantia nigra pars compacta R2* was higher in all PD subgroups (group, P???0.006), but showed a significantly faster increase only in later-stage PD (time?×?group, P?<?0.0001) that correlated with changes in nonmotor symptoms (r?=?0.746, P?=?0.002). Baseline substantia nigra pars reticulata quantitative susceptibility mapping was higher in middle-stage PD and later-stage PD (group, P???0.002), but showed a longitudinal decrease (time?×?group, P?=?0.004) only in later-stage PD that correlated with changes in motor signs (r?=?0.837, P?<?0.001). CONCLUSION:Susceptibility MRI revealed distinct patterns of PD progression in the substantia nigra pars compacta and substantia nigra pars reticulata. The different patterns are particularly clear in later-stage patients. These findings may resolve past controversies and have implications in the pathophysiological processes during PD progression. © 2018 International Parkinson and Movement Disorder Society.

Project description:BackgroundParkinson's disease (PD) is the most common neurodegenerative disorder involving the motor system. Although not being the only region involved in PD, affection of the substantia nigra and its projections is responsible for some of the most debilitating features of the disease. To further advance a comprehensive understanding of nigral pathology, we conducted a tissue based comparative proteome study of healthy and diseased human substantia nigra.ResultsThe gross number of differentially regulated proteins in PD was 221. In total, we identified 37 proteins, of which 16 were differentially expressed. Identified differential proteins comprised elements of iron metabolism (H-ferritin) and glutathione-related redox metabolism (GST M3, GST P1, GST O1), including novel redox proteins (SH3BGRL). Additionally, many glial or related proteins were found to be differentially regulated in PD (GFAP, GMFB, galectin-1, sorcin), as well as proteins belonging to metabolic pathways sparsely described in PD, such as adenosyl homocysteinase (methylation), aldehyde dehydrogenase 1 and cellular retinol-binding protein 1 (aldehyde metabolism). Further differentially regulated proteins included annexin V, beta-tubulin cofactor A, coactosin-like protein and V-type ATPase subunit 1. Proteins that were similarly expressed in healthy or diseased substantia nigra comprised housekeeping proteins such as COX5A, Rho GDI alpha, actin gamma 1, creatin-kinase B, lactate dehydrogenase B, disulfide isomerase ER-60, Rab GDI beta, methyl glyoxalase 1 (AGE metabolism) and glutamine synthetase. Interestingly, also DJ-1 and UCH-L1 were expressed similarly. Furthermore, proteins believed to serve as internal standards were found to be expressed in a constant manner, such as 14-3-3 epsilon and hCRMP-2, thus lending further validity to our results.ConclusionUsing an approach encompassing high sensitivity and high resolution, we show that alterations of SN in PD include many more proteins than previously thought. The results point towards a heterogeneous aetiopathogenesis of the disease, including alterations of GSH-related proteins as well as alterations of proteins involved in retinoid metabolism, and they indicate that proteins involved in familial PD may not be differentially regulated in idiopathic Parkinson's disease.

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Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease.

Publications

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease.

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