α-Synuclein is a presynaptic neuronal protein that is linked genetically and neuropathologically to Parkinson's disease (PD). α-Synuclein may contribute to PD pathogenesis in a number of ways, but it is generally thought that its aberrant soluble oligomeric conformations, termed protofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including synaptic function. Furthermore, secreted α-synuclein may exert deleterious effects on neighboring cells, including seeding of aggregation, thus possibly contributing to disease propagation. Although the extent to which α-synuclein is involved in all cases of PD is not clear, targeting the toxic functions conferred by this protein when it is dysregulated may lead to novel therapeutic strategies not only in PD, but also in other neurodegenerative conditions, termed synucleinopathies.

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α-Synuclein in Parkinson’s Disease

Unique Properties of Mesoprefrontal Neurons within a Dual Mesocorticolimbic Dopamine System

Parkinson’s disease is a chronic progressive neurodegenerative disorder characterized by resting tremor, slowness of movements, rigidity, gait disturbance and postural instability. Most investigations on Parkinson’s disease focused on the basal ganglia, whereas the cerebellum has often been overlooked. However, increasing evidence suggests that the cerebellum may have certain roles in the pathophysiology of Parkinson’s disease. Anatomical studies identified reciprocal connections between the basal ganglia and cerebellum. There are Parkinson’s disease–related pathological changes in the cerebellum. Functional or morphological modulations in the cerebellum were detected related to akinesia/rigidity, tremor, gait disturbance, dyskinesia and some non-motor symptoms. It is likely that the major roles of the cerebellum in Parkinson’s disease include pathological and compensatory effects. Pathological changes in the cerebellum might be induced by dopaminergic degeneration, abnormal drives from the basal ganglia and dopaminergic treatment, and may account for some clinical symptoms in Parkinson’s disease. The compensatory effect may help maintain better motor and non-motor functions. The cerebellum is also a potential target for some parkinsonian symptoms. Our knowledge about the roles of the cerebellum in Parkinson’s disease remains limited, and further attention to the cerebellum is warranted.

The cerebellum in Parkinson’s disease

Multiple hit hypotheses for dopamine neuron loss in Parkinson's disease

G protein-gated inwardly rectifying potassium (GIRK) channels hyperpolarize neurons in response to activation of many different G protein-coupled receptors and thus control the excitability of neurons through GIRK-mediated self-inhibition, slow synaptic potentials and volume transmission. GIRK channel function and trafficking are highly dependent on the channel subunit composition. Pharmacological investigations of GIRK channels and studies in animal models suggest that GIRK activity has an important role in physiological responses, including pain perception and memory modulation. Moreover, abnormal GIRK function has been implicated in altering neuronal excitability and cell death, which may be important in the pathophysiology of diseases such as epilepsy, Down's syndrome, Parkinson's disease and drug addiction. GIRK channels may therefore prove to be a valuable new therapeutic target.

/pdf/emerging-roles-for-g-protein-gated-inwardly-rectifying-5d123yln9h.pdf

Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease

The selective degeneration of dopaminergic (DA) midbrain neurons in the substantia nigra (SN) is a hallmark of Parkinson disease. DA neurons in the neighboring ventral tegmental area (VTA) are significantly less affected. The mechanisms for this differential vulnerability of DA neurons are unknown. We identified selective activation of ATP-sensitive potassium (K-ATP) channels as a potential mechanism. We show that in response to parkinsonism-inducing toxins, electrophysiological activity of SN DA neurons, but not VTA DA neurons, is lost owing to activation of K-ATP channels. This selective K-ATP channel activation is controlled by differences in mitochondrial uncoupling between SN and VTA DA neurons. Genetic inactivation of the K-ATP channel pore-forming subunit Kir6.2 resulted in a selective rescue of SN but not VTA DA neurons in two mechanistically distinct mouse models of dopaminergic degeneration, the neurotoxicological 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model and the mutant weaver mouse. Thus, K-ATP channel activation has an unexpected role in promoting death of DA neurons in chronic disease.

K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons

The presynaptic protein alpha-synuclein is involved in several neurodegenerative diseases, including Parkinson's disease (PD). In rare familial forms of PD, causal mutations (PARK1) as well as multiplications (PARK4) of the alpha-synuclein gene have been identified. In sporadic, idiopathic PD, abnormal accumulation and deposition of alpha-synuclein might also cause degeneration of dopaminergic midbrain neurons, the clinically most relevant neuronal population in PD. Thus, cell-specific quantification of alpha-synuclein expression-levels in dopaminergic neurons from idiopathic PD patients in comparison to controls would provide essential information about contributions of alpha-synuclein to the etiology of PD. However, a number of previous studies addressing this question at the tissue-level yielded varying results regarding alpha-synuclein expression. To increase specificity, we developed a cell-specific approach for mRNA quantification that also took into account the important issue of variable RNA integrities of the individual human postmortem brain samples. We demonstrate that PCR -amplicon size can confound quantitative gene-expression analysis, in particular of partly degraded RNA. By combining optimized UV-laser microdissection- and quantitative RT-PCR-techniques with suitable PCR assays, we detected significantly elevated alpha-synuclein mRNA levels in individual, surviving neuromelanin- and tyrosine hydroxylase-positive substantia nigra dopaminergic neurons from idiopathic PD brains compared to controls. These results strengthen the pathophysiologic role of transcriptional dysregulation of the alpha-synuclein gene in sporadic PD.

https://www.uni-ulm.de/fileadmin/website_uni_ulm/med.inst.010/bliss-pdf/NAR2008Liss.pdf

Olga Haeckel

Papers

K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons

Elevated α-synuclein mRNA levels in individual UV-laser-microdissected dopaminergic substantia nigra neurons in idiopathic Parkinson's disease

Behavioral phenotyping of mice lacking the K ATP channel subunit Kir6.2.

KATP channels control the differential vulnerability of dopaminergic midbrain neurons in a chronic MPTP-model of Parkinson's disease