Milestones in PD Genetics

Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, and German Center for Neurodegenerative Diseases, Tübingen, Germany.
Movement Disorders (Impact Factor: 5.63). 05/2011; 26(6):1042-8. DOI: 10.1002/mds.23637
Source: PubMed

ABSTRACT Over the last 25 years, genetic findings have profoundly changed our views on the etiology of Parkinson's disease. Linkage studies and positional cloning strategies have identified mutations in a number of genes that cause several monogenic autosomal-dominant or autosomal-recessive forms of the disorder. Although most of these Mendelian forms of Parkinson's disease are rare, whole-genome association studies have more recently provided convincing evidence that low-penetrance variants in at least some of these, but also in several other genes, play a direct role in the etiology of the common sporadic disease as well. In addition, rare variants with intermediate-effect strengths in genes such as Gaucher's disease-associated glucocerebrosidase A have been discovered as important risk factors. "Next-generation" sequencing technologies are expected by some to identify many more of these variants. Thus, an increasingly complex network of genes contributing in different ways to disease risk and progression is emerging. These findings may provide the "genetic entry points" to identify molecular targets and readouts necessary to design rational disease-modifying treatments.

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    • "mitochondrial toxins such as rotenone, which is still widely used in bulk amounts for river treatment to fight fish parasites (Finlayson et al., 2014)) as well as genetic factors (e.g. PARK-genes), as summarized in detail in excellent reviews (Hirsch and Hunot, 2009; Hardy, 2010; Alves da Costa and Checler, 2011; Collier et al., 2011; Gasser et al., 2011; Surmeier et al., 2012; Moskvina et al., 2013; Ramanan and Saykin, 2013; Singleton et al., 2013; Sulzer and Surmeier, 2013). In essence, activity-related cellular Ca 2+ load, mitochondrial DNA deletions and mitochondrial dysfunction, as well as oxidative and metabolic stress are particularly important trigger factors for PD (Bender et al., 2006; Guzman et al., 2010; Alves da Costa and Checler, 2011; Collier et al., 2011; Shulman et al., 2011; Watfa et al., 2011; Coskun et al., 2012; Surmeier and Schumacker, 2013; Checler and Alves da Costa, 2014; Parlato and Liss, 2014; Phillipson, 2014). "
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    ABSTRACT: Dopamine (DA) releasing midbrain neurons are essential for multiple brain functions, such as voluntary movement, working memory, emotion and cognition. DA midbrain neurons within the substantia nigra (SN) and the ventral tegmental area (VTA) exhibit a variety of distinct axonal projections and cellular properties, and are differentially affected in diseases like schizophrenia, attention deficit hyperactivity disorder, and Parkinson's disease (PD). Apart from having diverse functions in health and disease states, DA midbrain neurons display distinct electrical activity patterns, crucial for DA release. These activity patterns are generated and modulated by specific sets of ion channels. Recently, two ion channels have been identified, not only contributing to these activity patterns and to functional properties of DA midbrain neurons, but also seem to render SN DA neurons particularly vulnerable to degeneration in PD and its animal models: L-type calcium channels (LTCCs) and ATP-sensitive potassium channels (K-ATPs). In this review, we focus on the emerging physiological and pathophysiological roles of these two ion channels (and their complex interplay with other ion channels), particularly in highly vulnerable SN DA neurons, as selective degeneration of these neurons causes the major motor symptoms of PD.
    Neuroscience 10/2014; 284. DOI:10.1016/j.neuroscience.2014.10.037 · 3.33 Impact Factor
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    • "Pacemaker activity of SN DA neurons is inhibited by dopamine itself, via therapeutically relevant dopamine D2-autoreceptors, through activation of inwardly rectifying potassium channels (GIRK2) (Luscher and Slesinger, 2010; Anzalone et al., 2012; Gantz et al., 2013). Mouse models with mutations in PARK genes, which lead to familial forms of Parkinson's disease (Gasser et al., 2011), show altered substantia nigra dopamine D2-autoreceptor responses (Goldberg et al., 2005; Tong et al., 2009), further linking D2-autoreceptor function to Parkinson's disease pathology. "
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    ABSTRACT: Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson's disease. Their selective loss causes the major motor symptoms of Parkinson's disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson's disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca(2+) channels both contribute to Parkinson's disease pathology. L-type Ca(2+) channel blockers protect SN DA neurons from degeneration in Parkinson's disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson's disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson's disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson's disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson's disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological and genetic tools, we identified that the expression of this sensitized D2-autoreceptor phenotype required Cav1.3 L-type Ca(2+) channel activity, internal Ca(2+), and the interaction of the neuronal calcium sensor NCS-1 with D2-autoreceptors. Thus, we identified a first physiological function of Cav1.3 L-type Ca(2+) channels in SN DA neurons for homeostatic modulation of their D2-autoreceptor responses. L-type Ca(2+) channel activity however, was not important for pacemaker activity of mouse SN DA neurons. Furthermore, we detected elevated substantia nigra dopamine messenger RNA levels of NCS-1 (but not Cav1.2 or Cav1.3) after cocaine in mice, as well as in remaining human SN DA neurons in Parkinson's disease. Thus, our findings provide a novel homeostatic functional link in SN DA neurons between Cav1.3- L-type-Ca(2+) channels and D2-autoreceptor activity, controlled by NCS-1, and indicate that this adaptive signalling network (Cav1.3/NCS-1/D2/GIRK2) is also active in human SN DA neurons, and contributes to Parkinson's disease pathology. As it is accessible to pharmacological modulation, it provides a novel promising target for tuning substantia nigra dopamine neuron activity, and their vulnerability to degeneration.
    Brain 06/2014; 137(8). DOI:10.1093/brain/awu131 · 10.23 Impact Factor
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    • "Loss of DA neurons is usually preceded by a cellular accumulation of alphasynuclein-positive protein conglomerates, so-called Lewy bodies (Spillantini et al., 1997). The cause for PD is still unclear, however mitochondrial, proteasomal as well as lysosomal dysfunctions are relevant triggers (Gasser et al., 2011). Depending on the ethnic population, approximately 10%e30% of familial forms of PD are caused by mutations in one of the several PARK gene loci (PARK1- 15) (Shulman et al., 2011). "
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    ABSTRACT: Progressive loss of substantia nigra dopamine neurons (SN DA) is a hallmark of aging and of Parkinson's disease (PD). Mutations in PARK genes cause familial PD forms. Increased expression of alpha-synuclein (PARK4) is a disease-triggering event in familial PD and also observed in SN DA neurons in sporadic PD but related transcriptional changes are unknown. With optimized single-cell quantitative real-time polymerase chain reaction analysis, we compared messenger RNA and microRNA levels in SN DA neurons from sporadic PD patients and controls. Non-optimally matched donor ages and RNA integrities are common problems when analyzing human samples. We dissected the influence of distinct ages and RNA integrities of our samples by applying a specifically-optimized, linear-mixed-effects model to quantitative real-time polymerase chain reaction-data. We identified that elevated alpha-synuclein messenger RNA levels in SN DA neurons of human PD brains were positively correlated with corresponding elevated levels of mRNAs for functional compensation of progressive SN DA loss and for enhanced proteasomal (PARK5/UCHL1) and lysosomal (PARK9/ATPase13A2) function, possibly counteracting alpha-synuclein toxicity. In contrast, microRNA miR-133b levels, previously implicated in transcriptional dysregulation in PD, were not altered in SN DA neurons in PD.
    Neurobiology of aging 03/2014; 35(10). DOI:10.1016/j.neurobiolaging.2014.03.016 · 4.85 Impact Factor
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