Article

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.
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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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    • "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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