A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years' experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies

Objectives: The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare chronic inflammatory disorders of childhood, affecting muscle, skin and other organs. There is a severe lack of evidence base for current treatment protocols in juvenile myositis. The rarity of these conditions means that multicentre collaboration is vital to facilitate studies of pathogenesis, treatment and disease outcomes. We have established a national registry and repository for childhood IIM, which aims to improve knowledge, facilitate research and clinical trials, and ultimately to improve outcomes for these patients. Methods: A UK-wide network of centres and research group was established to contribute to the study. Standardized patient assessment, data collection forms and sample protocols were agreed. The Biobank includes collection of peripheral blood mononuclear cells, serum, genomic DNA and biopsy material. An independent steering committee was established to oversee the use of data/samples. Centre training was provided for patient assessment, data collection and entry. Results: Ten years after inception, the study has recruited 285 children, of which 258 have JDM or juvenile PM; 86% of the cases have contributed the biological samples. Serial sampling linked directly to the clinical database makes this a highly valuable resource. The study has been a platform for 20 sub-studies and attracted considerable funding support. Assessment of children with myositis in contributing centres has changed through participation in this study. Conclusions: This establishment of a multicentre registry and Biobank has facilitated research and contributed to progress in the management of a complex group of rare muscloskeletal conditions

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.</p

Personality development in monozygotic twins of varying IQ discordance

The present study sought to investigate the personality-intelligence association by using longitudinal MZ twin data to examine if intelligence and personality are developmentally linked. If twins discordant for IQ in childhood grew up to differ more in personality than twins of very similar intelligence, it would support theories of personality and intelligence that posit a developmental interaction between the two and a non-shared environmental influence can be inferred. It was also investigated if twins concordant for either low or high childhood IQ had personalities that on average differed more from their co-twins later in life. The sample consisted of 789 MZ twin pairs participating in the Minnesota Twin Family Study. The analysis used a series of one-way ANOVAs comparing the mean personality difference scores at ages 17 and 25 of groups of twins discordant for IQ to twins concordant for high or low IQ. Twins discordant for childhood IQ did not show a pattern of more discordance in personality at either age 17 or 25. When IQ was divided into performance IQ and verbal IQ conflicting results were obtained. The final finding was that differences were greater between twins concordant for higher than for lower intelligence on the traits Wellbeing and Social Potency. This tentatively suggests that a positive, outgoing and social side to Extraversion is more variable at higher levels of intelligence. There is no straight forward interpretation of the overall lack of relation between early intelligence and subsequent personality. Interpretations related to limitations in the study design and an absence of a direct influence of intelligence on personality are discussed

Investigation of repeat-associated non-AUG translation and dipeptide repeat proteins in C9orf72-associated ALS/FTD

A hexanucleotide repeat expansion in the gene C9orf72 is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion causes intranuclear RNA foci and repeat-associated non-AUG (RAN) translation of five aberrant dipeptide repeat proteins (DPRs). Both RNA foci and DPRs are widely distributed in the patient brain, alongside reduced expression of the C9orf72 protein, involved in proteostasis, vesicle trafficking and immunity. TDP-43 neuropathology arises in nearly all cases and correlates with clinical symptoms and neurodegeneration. The primary cause of C9orf72-associated ALS/FTD is unknown, as the putative pathomechanisms may synergise to exert neurotoxicity. Evidence supports a pathogenic role of DPRs, although endogenous neuronal RAN translation of DPRs is not well understood. Moreover, the effects of the mutation on selectively vulnerable motor neurons are incompletely understood, e.g. in terms of functional connectivity development and synaptic integrity. Consequently, the overarching aims of this thesis are to uncover mechanisms regulating endogenous neuronal DPR levels and to identify mutation-related and DPR-specific changes to motor neuron phenotypes to ultimately aid discovery of therapeutic targets, as currently no effective therapeutics exist. First, a C9orf72 ALS/FTD patient-derived iPSC-motor neuron model was generated to investigate early molecular and functional phenotypes and endogenous RAN translation modifiers, which revealed network hyposynchrony and a novel pathway involved in RAN translation. Next, neuromuscular junction integrity was assessed in the context of selective DPR expression, in novel C9orf72 ALS/FTD knock-in mouse models with temporally and spatially relevant expression of DPRs driven by the mouse C9orf72 promoter and concomitant C9orf72 haploinsufficiency, which led to discovery of presynaptic structural abnormalities at neuromuscular junctions. This work contributes new insights into the pathomechanisms of C9orf72 ALS/FTD within the motor system and new directions in the search for therapeutic targets, with potential relevance for other neurodegenerative diseases and polynucleotide repeat disorders