Inside out: the role of nucleocytoplasmic transport in ALS and FTLD

Neurodegenerative diseases are characterized by the presence of protein inclusions with a different protein content depending on the type of disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are no exceptions to this common theme. In most ALS and FTLD cases, the predominant pathological species are RNA-binding proteins. Interestingly, these proteins are both depleted from their normal nuclear localization and aggregated in the cytoplasm. This key pathological feature has suggested a potential dual mechanism with both nuclear loss of function and cytoplasmic gain of function being at play. Yet, why and how this pathological cascade is initiated in most patients, and especially sporadic cases, is currently unresolved. Recent breakthroughs in C9orf72 ALS/FTLD disease models point at a pivotal role for the nuclear transport system in toxicity. To address whether defects in nuclear transport are indeed implicated in the disease, we reviewed two decades of ALS/FTLD literature and combined this with bioinformatic analyses. We find that both RNA-binding proteins and nuclear transport factors are key players in ALS/FTLD pathology. Moreover, our analyses suggest that disturbances in nucleocytoplasmic transport play a crucial initiating role in the disease, by bridging both nuclear loss and cytoplasmic gain of functions. These findings highlight this process as a novel and promising therapeutic target for ALS and FTLD.status: publishe

Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics

Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2α phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD

Intérêt ophtalmologique du groupe des dyslipidoses

info:eu-repo/semantics/publishe

Les lésions cérébrales et les troubles mentaux dans la sclérose latérale amyotrophique

Doctorat en sciences médicalesinfo:eu-repo/semantics/nonPublishe

Associations anatomo-cliniques :dégénérescence pigmentaire pallido-nigrique (Hallervorden-Spatz) et encéphalite léthargique chronique

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Le poids du litre normal de butane normal. Son coefficient de compressibilité. 1ère partie. Méthode employée pour la préparation du gaz. 2e partie. Appareils pour la détermination de la densité et résultats de mesures

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

L'hystérie et les fonctions diencéphaliques: Etude neurologique

info:eu-repo/semantics/publishe