Identification of genes in trinucleotide repeat RNA toxicity pathways in C. elegans

Myotonic dystrophy disorders are caused by expanded CUG repeats in non-coding regions. To reveal mechanisms of CUG repeat pathogenesis we used C. elegans expressing CUG repeats to identify gene inactivations that modulate CUG repeat toxicity. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and modulate formation of nuclear RNA foci by CUG repeats. These genes regulated CUG repeat-induced toxicity through distinct mechanisms including RNA export and RNA clearance, suggesting that CUG repeat toxicity is mediated by multiple pathways. A subset is shared with other degenerative disorders. The nonsense-mediated mRNA decay (NMD) pathway plays a conserved role regulating CUG repeat RNA transcript levels and toxicity, and NMD recognition of toxic RNAs depends on 3′UTR GC nucleotide content. Our studies suggest a broader surveillance role for NMD where variations in this pathway influence multiple degenerative diseases

Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models

ALS is a devastating neurodegenerative disease primarily affecting motor neurons. Mutations in TDP-43 cause some forms of the disease, and cytoplasmic TDP-43 aggregates accumulate in degenerating neurons of most ALS patients. Thus, strategies aimed at targeting the toxicity of cytoplasmic TDP-43 aggregates may be effective. Here we report results from two genome-wide loss-of-function TDP-43 toxicity suppressor screens in yeast. The strongest suppressor of TDP-43 toxicity was deletion of Dbr1, which encodes RNA lariat debranching enzyme. We show that in the absence of Dbr1 enzymatic activity intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP-43 away from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of Dbr1 in a human neuronal cell line or in primary rodent neurons is also sufficient to rescue TDP-43 toxicity. Our findings provide insight into TDP-43 cytotoxicity and suggest decreasing Dbr1 activity could be a potential therapeutic approach for ALS

The Individual Rehabilitation Project as the core of person-centered rehabilitation: the Physical and Rehabilitation Medicine Section and Board of the European Union of Medical Specialists Framework for Rehabilitation in Europe

To facilitate the interaction between the health professional and the patient, a framework to guide the rehabilitation process is needed. This framework would encompass three interwoven aspects: the rehabilitation management plan, Individual Rehabilitation Project (IRP), and rehabilitation cycle(s). All three framework aspects focus on the patient and on the aim of rehabilitation, i.e. to optimize a person's functioning across the continuum of care. An IRP is a multi-element, person-centered rehabilitation management scheme, in which rehabilitation is generally provided by a multiprofessional team under the leadership of a physical and rehabilitation medicine (PRM) physician, working in an interdisciplinary manner and together with the patient (or proxy). A reference system for operationalizing functioning and standardizing the process is the International Classification of Functioning, Disability and Health (ICF) - for assessing functioning needs, defining rehabilitation goals and outcomes. The objective of this paper is to present the IRP as a framework for rehabilitation in Europe (EUR-IRP). The specific aims are: 1) to introduce the IRP; and 2) to describe the framework components, elements and variables of the IRP. Demonstration projects (case studies) using the EUR-IRP will be conducted. The present paper presents the efforts to date for developing the EUR-IRP, a key part of the action plan of the PRM Section and Board of the European Union of Medical Specialists to implement the ICF systemwide across the care continuum. This paper serves as another step to bring together practice, science and governance in calling for contribution from rehabilitation clinicians and researchers and professional societies in PRM and beyond. © 2022 Edizioni Minerva Medica. All rights reserved

The mutational landscape of a prion-like domain

Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase.Work in B.L.’s lab was supported by a European Research Council (ERC) Consolidator grant (616434), the Spanish Ministry of Economy and Competitiveness (BFU2017-89488-P), the AXA Research Fund, the Bettencourt Schueller Foundation, and Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, SGR-831) G.G.T.’s lab was supported by the European Research Council (RIBOMYLOME_309545) and the Spanish Ministry of Economy and Competitiveness (BFU2014-55054-P and BFU2017-86970-P). We acknowledge support from the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013-2017’, the EMBL Partnership, and the CERCA Program/Generalitat de Catalunya. We thank Pablo Baeza Centurión, Xavier Salvatella, Alexandros Armaos and Benjamin Lang for discussion and assistance and the Eisenberg lab for help with the ZipperDB analysis