SUMMARY
Huntington disease (HD) is caused by a CAG·CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other poly-glutamine diseases.
SUMMARY
Several microsatellite-expansion diseases are characterized by the accumulation of RNA foci and RAN proteins raising the possibility of a mechanistic connection. We explored this question using myotonic dystrophy type 2, a multisystemic disease thought to be primarily caused by RNA gain-of-function effects. We demonstrate the DM2 CCTG•CAGG expansion expresses sense and antisense tetrapeptide poly-(LPAC) and poly-(QAGR) RAN proteins, respectively. In DM2 autopsy brains, LPAC is found in neurons, astrocytes and glia in grey matter and antisense QAGR proteins accumulate within white matter. LPAC and QAGR proteins are toxic to cells independent of RNA gain of function. RNA foci and nuclear sequestration of CCUG transcripts by MBNL1 is inversely correlated with LPAC expression. These data suggest a model, that involves nuclear retention of expansion RNAs by RNA-binding proteins (RBPs) and an acute phase in which expansion RNAs exceed RBP sequestration capacity, are exported to the cytoplasm and undergo RAN translation.
Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.
Amaç: Diz osteoartriti (OA) sık görülen ve neden olduğu ağrı ve sakatlık sonucunda sosyoekonomik yük bindiren bir hastalıktır. Türkiye Romatizma Araştırma ve Savaş Derneği (TRASD) OA tedavisi ile uğraşan hekimlere günlük klinik uygulamalarında yardımcı olmak amacıyla, uzman görüşleri ile desteklenmiş, ulusal "diz osteoartrit tedavisinde kanıta dayalı önerileri" hazırlamak için bir proje başlatmıştır. Objectives: Knee osteoarthritis (OA) is a common disease which causes pain, disability and great socioeconomic burden as a result. Turkish League Against Rheumatism (TLAR) initiated a project to prepare national, "evidence-based recommendations for the management of knee osteoarthritis" supported by expertopinion in order to assist the physicians who are interested in knee OA in their daily clinical practice.
Gereç ve yöntemler:
Materials and methods:The expert committee was composed of 25 academicians, 23 of whom were physical medicine and rehabilitation (PM&R) specialists (three also had rheumatology subspeciality) and two were orthopedic surgeons. At the first meeting, the previous guidelines were discussed, and 2008 Osteoarthritis Research Society International (OARSI) recommendations were decided to be taken as the fundamental template for national recommendations. Databases of the Pubmed, Embase, Cochrane, and Turkish Medical Index were used to search the literature, and this was carried out for the period between 2009-2010 for international publications since studies up to 2009 were present in the 2010 OARSI update. No limit was applied for searching of national publications. The selected relevant publications were graded according to evidence level and quality, and were sent to the members who were then asked to suggest propositions according to their experiences, knowledge, and review of the literature. After amalgamation and editing of new proposals, Delphi rounds were started. After five Delphi rounds, the propositions on which the members were in consensus, were discussed with regard to evidence and the "strength of recommendation" was determined by measuring on visual analog scale (VAS) for each proposal at the final meeting.Results: Nineteen propositions (one for general principles, nine for nonpharmacologic treatments, seven for pharmacologic treatments, and two for surgical treatments) were accepted as the "TLAR Evidence-Based Recommendations for the Management of Knee OA" in consensus as a result of Delphi rounds.
Conclusion:Evidence-based recommendations for the management of knee OA were developed by TLAR for the first time in our country. The recommendations should be updated regularly according to new evidence and insights. It is expected that physicians who are interested in knee OA will benefit greatly from this report in their daily clinical practice.
Autism spectrum disorder (ASD) is a highly prevalent and complex genetic disorder. The complex genetic make-up of ASD has been extensively studied and both common and rare genetic variants in up to 1000 genes have been linked to increased ASD risk. While these studies highlight the genetic complexity and begin to provide a window for delineating pathways at risk in ASD, the pathogenicity and specific contribution of many mutations to the disorder are poorly understood. Defining the convergent pathways disrupted by this large number of ASD-associated genetic variants will help to understand disease pathogenesis and direct future therapeutic efforts for the groups of patients with distinct etiologies. Here, we review some of the common regulatory pathways including chromatin remodeling, transcription, and alternative splicing that have emerged as common features from genetic and transcriptomic profiling of ASD. For each category, we focus on one gene (CHD8, FOXP1, and RBFOX1) that is significantly linked to ASD and functionally characterized in recent years. Finally, we discuss genetic and transcriptomic overlap between ASD and other neurodevelopmental disorders.
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