Inflammatory profile discriminates clinical subtypes in LRRK2-associated Parkinson's disease.

BACKGROUND AND PURPOSE: The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2 ) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes. METHODS: An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor. RESULTS: Patients classified as diffuse/malignant presented with the highest levels of the pro-inflammatory proteins interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 1-ß (MIP-1-ß) paralleled by high levels of the neurotrophic protein brain-derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis. CONCLUSIONS: Inflammation seems to be associated with the presence of a specific clinical subtype in PDLRRK2 that is characterized by a broad and more severely affected spectrum of motor and non-motor symptoms. The pro-inflammatory metabolites IL-8, MCP-1 and MIP-1-ß as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PDLRRK2 and predict progression.

Immunocytochemical studies of the interactions of cadherins and catenins in the early Xenopus embryo.

Linkage of cadherins to the cytoskeleton is crucial for their adhesive function. Since alpha- and beta-catenin play a key role in this linkage, these proteins are possible targets for processes that control cell-cell adhesion. To achieve a better understanding of the regulation of cell-cell adhesion in embryonic morphogenesis, we used immunohistology to investigate how in Xenopus blastomeres catenins respond to disturbances in the expression of maternal cadherins. Overexpression of myc-tagged maternal cadherin leads to a proportionate increase of the level of beta-catenin. The two proteins colocalize in the endoplasmic reticulum, in cytoplasmic vesicles, and along the cell membrane, indicating that the beta-catenin binds to overexpressed cadherin early in its passage to the plasma membrane. Expression of cadherin is essential for the stable presence of beta-catenin, as depletion from maternal cadherin mRNA leads to a complete loss of beta-catenin from the blastomeres. alpha-Catenin behaves differently. Overexpression of cadherin leaves the amount and localization of alpha-catenin largely unaffected, and additional cadherin inserts itself into the membrane without a proportionate rise in the level of membrane-bound alpha-catenin. However, cadherin mRNA depletion leads to a redistribution of alpha-catenin from the membrane to the cytoplasm. Thus, cadherin is required to localize alpha-catenin to the membrane, but the amount of alpha-catenin along the membrane seems to be restricted to a certain level which cannot be exceeded. The relevance of these observations for the regulation of cadherin-mediated cell adhesion in the Xenopus embryo is discussed. Additionally, we demonstrate that plakoglobin, like beta-catenin an armadillo repeat protein, shows neither accumulation after overexpression nor colocalization with the overexpressed cadherin.

Anteroposterior patterning and organogenesis of Xenopus laevis require a correct dose of germ cell nuclear factor (xGCNF).

The germ cell nuclear factor of Xenopus laevis (xGCNF; NR6A1) is a nuclear orphan receptor that is predominantly expressed during neurula and late tailbud stages. As a strategy to analyze the role of xGCNF in embryogenesis, we have induced a gain of function by overexpression of full-length (fl) GCNF and a functional inhibition by a dominant-negative (dn) GCNF. Early events of embryogenesis including gastrulation and neurulation were not affected and the expression of several early mesodermal markers was normal. Yet specific defects were observed upon organogenesis. Ectopic posterior overexpression of the full-length xGCNF caused posterior defects and disturbed somite formation. In contrast, expression of dnGCNF interfered with differentiation of the neural tube and affected the differentiation of anterior structures, including the cement gland and the eyes. Embryos affected by dnGCNF were rescued by coexpression of flGCNF. After expression of dnGCNF, mRNA encoding the the retinoic acid receptor xRAR gamma 2 was selectively suppressed anteriorly. From the distinct phenotypes obtained, we conclude that GCNF has an essential function in anteroposterior differentiation during organogenesis.