Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153640 (Cerebellum)
 1,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disorder with preferential affection of Purkinje neurons, which are known as integrators of calcium currents. The expansion of a polyglutamine (polyQ) domain in the RNA-binding protein ataxin-2 (ATXN2) is responsible for this disease, but the causal roles of deficient ATXN2 functions versus aggregation toxicity are still under debate. Here, we studied mouse mutants with Atxn2 knockout (KO) regarding their cerebellar global transcriptome by microarray and RT-qPCR, in comparison with data from Atxn2-CAG42-knock-in (KIN) mouse cerebellum. Global expression downregulations involved lipid and growth signaling pathways in good agreement with previous data. As a novel effect, downregulations of key factors in calcium homeostasis pathways (the transcription factor Rora, transporters Itpr1 and Atp2a2, as well as regulator Inpp5a) were observed in the KO cerebellum, and some of them also occurred subtly early in KIN cerebellum. The ITPR1 protein levels were depleted from soluble fractions of cerebellum in both mutants, but accumulated in its membrane-associated form only in the SCA2 model. Coimmunoprecipitation demonstrated no association of ITPR1 with Q42-expanded or with wild-type ATXN2. These findings provide evidence that the physiological functions and protein interactions of ATXN2 are relevant for calcium-mediated excitation of Purkinje cells as well as for ATXN2-triggered neurotoxicity. These insights may help to understand pathogenesis and tissue specificity in SCA2 and other polyQ ataxias like SCA1, where inositol regulation of calcium flux and RORalpha play a role.
Cerebellum 2017 02
PMID:Atxn2 Knockout and CAG42-Knock-in Cerebellum Shows Similarly Dysregulated Expression in Calcium Homeostasis Pathway. 2686 65

LIN28B is a homologue of the RNA-binding protein LIN28A and regulates gene expression during development and carcinogenesis. It is strongly upregulated in a variety of brain tumors, such as medulloblastoma, embryonal tumor with multilayered rosettes (ETMR), atypical teratoid/rhabdoid tumor (AT/RT), or glioblastoma, but the effect of an in vivo overexpression of LIN28B on the developing central nervous system is unknown. We generated transgenic mice that either overexpressed Lin28b in Math1-positive cerebellar granule neuron precursors or in a broad range of Nestin-positive neural precursors. Sections of the cerebellar vermis from adult Math1-Cre::lsl-Lin28b mice had an additional subfissure in lobule IV. Vermes from p0 and p7 Nestin-Cre::lsl-Lin28b mice appeared normal, but we found a pronounced vermal hypersublobulation at p15 and p21 in these mice. Also, the external granule cell layer (EGL) was thicker at p15 than in controls, contained more proliferating cells, and persisted up to p21. Consistently, some Pax6- and NeuN-positive cells were present in the EGL of Nestin-Cre::lsl-Lin28b mice even at p21, and we detected more NeuN-positive granule neuron precursors in the molecular layer (ML) as compared to control. Finally, we found some residual Pax2-positive precursors of inhibitory interneurons in the ML of Nestin-Cre::lsl-Lin28b mice at p21, which have already disappeared in controls. We conclude that while overexpression of LIN28B in Nestin-positive cells does not lead to tumor formation, it results in a protracted development of granule cells and inhibitory interneurons and leads to a hypersublobulation of the cerebellar vermis.
Cerebellum 2017 02
PMID:Overexpression of Lin28b in Neural Stem Cells is Insufficient for Brain Tumor Formation, but Induces Pathological Lobulation of the Developing Cerebellum. 2703 94