Milestones in PD genetics.
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.
SourceAvailable from: Saskia Biskup[Show abstract] [Hide abstract]
ABSTRACT: Mutations within the LRRK2 gene have been identified in Parkinson's disease (PD) patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human cell systems. We generated and characterized a novel transgenic mouse model expressing physiological levels of human wild type and G2019S-mutant LRRK2. No neuronal loss or neurodegeneration was detected in midbrain dopamine neurons at the age of 12 months. Postnatal hippocampal neurons derived from transgenic mice showed no alterations in the seven parameters examined concerning neurite outgrowth sampled automatically on several hundred neurons using high content imaging. Treatment with the kinase inhibitor LRRK2-IN-1 resulted in no significant changes in the neurite outgrowth. In human fibroblasts we analyzed whether pathogenic LRRK2 mutations change cytoskeleton functions such as cell adhesion. To this end we compared the adhesion characteristics of human skin fibroblasts derived from six PD patients carrying one of three different pathogenic LRRK2 mutations and from four age-matched control individuals. The mutant LRRK2 variants as well as the inhibition of LRRK2 kinase activity did not reveal any significant cell adhesion differences in cultured fibroblasts. In summary, our results in both human and mouse cell systems suggest that neither the expression of wild type or mutant LRRK2, nor the inhibition of LRRK2 kinase activity affect neurite complexity and cellular adhesion.PLoS ONE 01/2015; 10(4):e0118947. DOI:10.1371/journal.pone.0118947 · 3.53 Impact Factor
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ABSTRACT: The approach to early Parkinson's disease denotes the communication of the diagnosis and important decisions, such as when and how to start treatment. Evidence based medicine and guidelines indicate which drugs have robust evidence of efficacy and tolerability in this specific population. However, de-novo patients may show different characteristics and they may be in a different phase of their disease.In this review, we will give an insight into the appropriate time therapy should be started and the actual knowledge about disease modification therapies. Moreover, the drugs indicated for early treatment will be considered and an indication for the use of these drugs will be given with the support of the actual knowledge.
Article: Genetik der Parkinson-Krankheit[Show abstract] [Hide abstract]
ABSTRACT: Neben 9 eindeutig gesicherten monogenen Parkinson-Formen gibt es zahlreiche bekannte Risiko- oder protektive Genvarianten, die das Risiko für eine Parkinson-Erkrankung modulieren. Unter den monogenen Formen folgen 3 (PARK1/PARK4, PARK8, PARK17) einem autosomal-dominanten Erbgang und 6 einem rezessiven Vererbungsmuster (PARK2, PARK6, PARK7, PARK9, PARK14, PARK15). Ebenfalls 6 Formen gehen mit einem der idiopathischen Parkinson-Krankheit sehr ähnlichen klinischen Bild einher (PARK1/PARK4, PARK2, PARK6, PARK7, PARK8, PARK17), darunter sind PARK8 mit Mutationen im LRRK2-Gen und spätem Krankheitsbeginn bzw. PARK2 mit Mutationen im Parkin-Gen und frühem Erkrankungsalter die weitaus häufigsten. Pathophysiologisch stehen bei den monogenen Formen wie auch bei der idiopathischen Parkinson-Krankheit Mechanismen der oxidativen Modifikation, des gestörten Proteinabbaus sowie der mitochondrialen Dysfunktion im Mittelpunkt, sodass die monogenen Parkinson-Formen als humane Modellerkrankungen für die idiopathische Form dienen können. Abstract In addition to the nine well-defined monogenic forms of Parkinson’s disease, there are numerous known genetic risk and protective variants that modulate the risk of Parkinson’s disease. Among the monogenic forms, three (PARK1/PARK4, PARK8, PARK17) follow an autosomal dominant mode of inheritance, whereas six are recessively inherited (PARK2, PARK6, PARK7, PARK9, PARK14, PARK15). Six forms have clinical characteristics very similar to those of idiopathic Parkinson’s disease (PARK1/PARK4, PARK2, PARK6, PARK7, PARK8, PARK17). Among the latter forms, late-onset PARK8 with mutations in the LRRK2 gene and early-onset PARK2 caused by mutations in the Parkin gene are by far the most common. Both the monogenic and the idiopathic forms of Parkinson’s disease share common pathophysiological mechanisms involving oxidative modification, impaired protein degradation and mitochondrial dysfunction. Therefore, monogenic forms of Parkinson’s disease can serve as human model diseases for the idiopathic forms.Medizinische Genetik 06/2013; 25(2):215-220. DOI:10.1007/s11825-013-0386-8 · 0.09 Impact Factor