CRMP1 protein complexes modulate polyQ-mediated Htt aggregation and toxicity in neurons
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Mathematisch-Naturwissenschaftliche Fakultät I
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Abstract
Chorea Huntington (HD) ist eine neurodegenerative Erkrankung, die durch Ablagerungen von N-terminal Polyglutamin-reichen Huntingtin (Htt) -Fragmenten in den betroffenen Neuronen charakterisiert ist. Das mutierte Htt (mHtt) Protein wird ubiquitär exprimiert. Das zellspezifische Absterben von „medium-sized spiny neurons“ (MSN) wird jedoch im Striatum von HD Patienten verursacht (Albin, 1995). Es wird angenommen, dass Striatum-spezifische Proteine, die mit Htt interagieren, eine wichtige Rolle in der Pathogenese von HD spielen (Ross, 1995). Protein-Protein-Interaktionsstudien haben gezeigt, dass einige der Htt-Interaktionspartner mit unlöslichen Htt-Ablagerungen in den Gehirnen von HD-Patienten kolokalisieren und die Bildung von Protein-Aggregaten beeinflussen (Goehler, 2004). Kürzlich wurde durch die Integration von Genexpressions- und Interaktionsdaten ein Striatum-spezifisches Protein-Interaktionsnetzwerk erstellt (Chaurasia, unveröffentlichte Daten). Eines der identifizierten Proteine ist CRMP1 (collapsin response mediator protein 1), das spezifisch in Neuronen exprimiert wird und möglicherweise eine wichtige Rolle bei der Pathogenese von HD spielt. Experimentelle Untersuchungen mithilfe eines Filter-Retardationsassays zeigten, dass CRMP1 die Anordnung von Htt zu fibrillären, SDS-unlöslichen Aggregaten verringert. Durch Rasterkraftmikroskopie wurde der direkte Effekt von CRMP1 auf den Aggregationsprozess von Htt bestätigt. Ko-Immunopräzipitationsstudien zeigten, dass CRMP1 und Htt in Säugerzellen unter physiologischen Bedingungen miteinander interagieren. Es wurde nachgewiesen, dass CRMP1 die Polyglutamin-abhängige Aggregation und Toxizität von Htt in Zell- und Drosophila-Modellen von HD moduliert. Außerdem konnte CRMP1 in neuronalen Ablagerungen in R6/2 Mäusegehirnen und dessen selektive Spaltung durch Calpaine gezeigt werden. Diese Ergebnisse deuten darauf hin, dass die Lokalisation und Funktion von CRMP1 bei der Krankheitsentstehung verändert werden.
Huntington’s disease (HD) is a neurodegenerative disorder characterized by the accumulation of N-terminal polyglutamine (polyQ)-containing huntingtin (Htt) fragments in affected neurons. The mutant Htt (mHtt) protein is ubiquitously expressed but causes specific dysfunction and death of striatal medium-sized spiny neurons (MSNs) (Albin, 1995). It is assumed that striatum specific proteins interacting with Htt might play an important role in HD pathogenesis (Ross, 1995). Previous protein-protein interaction (PPI) studies demonstrated that many Htt-interacting proteins colocalize with insoluble Htt inclusions in HD brains and modulate the mHtt phenotype (Goehler 2004). A striatum-specific, dysregulated PPI network has been created recently by integrating PPI networks with information from gene expression profiling data (Chaurasia, unpublished data). One of the identified dysregulated proteins potentially involved in HD pathogenesis was the neuron-specific collapsin response-mediator protein 1 (CRMP1). Here, I show that CRMP1 reduces the self-assembly of SDS-insoluble mHtt protein aggregates in vitro, indicating a direct role of CRMP1 on the mHtt aggregation process. Coimmunoprecipitation studies showed that CRMP1 and Htt associate in mammalian cells under physiological conditions. In addition, CRMP1 localizes to abnormal neuronal inclusions and efficiently modulates polyQ-mediated Htt aggregation and toxicity in cell and Drosophila models of HD. This suggests that dysfunction of the protein is crucial for disease pathogenesis. Finally, I observed that CRMP1 localizes to neuronal inclusions and is selectively cleaved by calpains in R6/2 mouse brains, indicating that its distribution and function are altered in pathogenesis. In conclusion, this study presents new findings on the function of CRMP1 and its role in the pathogenesis of HD. The protein interacts with Htt and modulates its aggregation and toxicity, in this way influencing the molecular course of the disease.
Huntington’s disease (HD) is a neurodegenerative disorder characterized by the accumulation of N-terminal polyglutamine (polyQ)-containing huntingtin (Htt) fragments in affected neurons. The mutant Htt (mHtt) protein is ubiquitously expressed but causes specific dysfunction and death of striatal medium-sized spiny neurons (MSNs) (Albin, 1995). It is assumed that striatum specific proteins interacting with Htt might play an important role in HD pathogenesis (Ross, 1995). Previous protein-protein interaction (PPI) studies demonstrated that many Htt-interacting proteins colocalize with insoluble Htt inclusions in HD brains and modulate the mHtt phenotype (Goehler 2004). A striatum-specific, dysregulated PPI network has been created recently by integrating PPI networks with information from gene expression profiling data (Chaurasia, unpublished data). One of the identified dysregulated proteins potentially involved in HD pathogenesis was the neuron-specific collapsin response-mediator protein 1 (CRMP1). Here, I show that CRMP1 reduces the self-assembly of SDS-insoluble mHtt protein aggregates in vitro, indicating a direct role of CRMP1 on the mHtt aggregation process. Coimmunoprecipitation studies showed that CRMP1 and Htt associate in mammalian cells under physiological conditions. In addition, CRMP1 localizes to abnormal neuronal inclusions and efficiently modulates polyQ-mediated Htt aggregation and toxicity in cell and Drosophila models of HD. This suggests that dysfunction of the protein is crucial for disease pathogenesis. Finally, I observed that CRMP1 localizes to neuronal inclusions and is selectively cleaved by calpains in R6/2 mouse brains, indicating that its distribution and function are altered in pathogenesis. In conclusion, this study presents new findings on the function of CRMP1 and its role in the pathogenesis of HD. The protein interacts with Htt and modulates its aggregation and toxicity, in this way influencing the molecular course of the disease.
Description
Keywords
Aggregation, Neurodegenerative Erkrankung, Chorea Huntington (HD), Mutierte Huntingtin (mHtt), Polyglutamin, Zytotoxizität., Protein-Protein-Interaktionsnetzwerk, CRMP1 (Collapsin Response Mediator Protein 1), Aggregation, Neurodegenerative disorders, Huntington’s disease (HD), Mutant Huntingtin (mHtt), Polyglutamine, Cytotoxicity Protein-Protein Interaction Networks, CRMP1 (Collapsin Response Mediator Protein 1)
Dewey Decimal Classification
570 Biologie
Citation
Bounab, Yacine.(2010). CRMP1 protein complexes modulate polyQ-mediated Htt aggregation and toxicity in neurons. 10.18452/16185