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: 5.68).
05/2011; 26(6):1042-8. DOI: 10.1002/mds.23637
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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- "Until about 20 years ago, Parkinson's disease (PD) was considered the textbook example of a " non-genetic " disorder. With the identification of an increasing number of disease-causing mutations and a host of genetic risk factors, this view has fundamentally changed . Nevertheless, the known monogenic forms of PD are rare and all together account for less than 5 to 10% of PD cases in most populations. "
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ABSTRACT: An increasing proportion of the individual and population risk to develop Parkinson's disease (PD) can be explained by genetic variants of different effect strength, forming a continuum from rare high penetrance gain or loss of function mutations to relatively common genetic risk variants that only mildly modify disease risk. In the coming years, further advances in molecular genetic technologies, in particular the increasing use of next generation sequencing, is likely to generate a wealth of new knowledge about the genetic basis of PD. Although specific treatments for PD based on the underlying genetic etiology will probably not be available in the near future, genetic testing is therefore likely to play an increasing role, both in the counselling of individual patients and their families with respect to the expected disease course and recurrence risks, and in the stratification of patient groups in clinical trials. Thus, the usefulness of genetic testing strongly depends on question asked and needs to be considered within each particular setting.
Available from: Birgit Liss
- "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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- "Accumulation of aggregated α-synuclein to form Lewy bodies is a neuropathological hallmark for PD (Lees et al., 2009). Mutations in leucine-rich repeat kinase 2, LRRK2, gene are common genetic determinants of PD, with at least 20 different mutations identified to date causing late-onset, familial autosomal-dominant PD (Gasser et al., 2011; Greene, 2012). The most prevalent amino acid substitution mutation in LRRK2, G2019S, has been found in 1–2% of sporadic PD cases; with sporadic PD and LRRK2-associated PD being clinically and neurochemically indistinguishable (Healy et al., 2008). "
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ABSTRACT: LRRK2 is a protein that interacts with a plethora of signaling molecules, but the complexity of LRRK2 function presents a challenge for understanding the role of LRRK2 in the pathophysiology of Parkinson's disease (PD). Studies of LRRK2 using over-expression in transgenic mice have been disappointing, however, studies using invertebrate systems have yielded a much clearer picture, with clear effects of LRRK2 expression, knockdown or deletion in Caenorhabditis elegans and Drosophila on modulation of survival of dopaminergic neurons. Recent studies have begun to focus attention on particular signaling cascades that are a target of LRRK2 function. LRRK2 interacts with members of the mitogen activated protein kinase (MAPK) pathway and might regulate the pathway action by acting as a scaffold that directs the location of MAPK pathway activity, without strongly affecting the amount of MAPK pathway activity. Binding to GTPases, GTPase-activating proteins and GTPase exchange factors are another strong theme in LRRK2 biology, with LRRK2 binding to rac1, cdc42, rab5, rab7L1, endoA, RGS2, ArfGAP1, and ArhGEF7. All of these molecules appear to feed into a function output for LRRK2 that modulates cytoskeletal outgrowth and vesicular dynamics, including autophagy. These functions likely impact modulation of α-synuclein aggregation and associated toxicity eliciting the disease processes that we term PD.
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