Neuronal Transcriptome from C9orf72 Repeat Expanded Human Tissue is Associated with Loss of C9orf72 Function

A hexanucleotide G4C2 repeat expansion in C9orf72 is the most common genetic cause of familial and sporadic cases of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The mutation is associated with a reduction of C9orf72 protein and accumulation of toxic RNA and dipeptide repeat aggregates. The accumulation of toxic RNA has been proposed to sequester RNA binding proteins thereby altering RNA processing, consistent with previous transcriptome studies that have shown that the C9orf72 repeat expansion is linked to abundant splicing alterations and transcriptome changes. Here, we used a subcellular fractionation method and FACS to enrich for neuronal nuclei from C9orf72 repeat expanded post-mortem human ALS/FTD brains, and to remove neuronal nuclei with TDP-43 pathology which are observed in nearly all symptomatic C9orf72 repeat expanded cases. We show that the C9orf72 expansion is associated with relatively mild gene expression changes. Dysregulated genes were enriched for vesicle transport pathways, which is consistent with the known functions of C9orf72 protein. Further analysis suggests that the C9orf72 transcriptome is not driven by toxic RNA but is rather shaped by the depletion of pathologic TDP-43 nuclei and the loss of C9orf72 expression. These findings argue against RNA binding protein sequestration in neurons as a major contributor to C9orf72 mediated toxicity

How to use coping strategies and become more resilient

It is well recognised that the transition period from medical student to qualified doctor is a particularly demanding time. However, the life course of a doctor presents its own challenges of equal or greater significance and the job of a doctor is becoming increasingly difficult (Figley, Huggard and Rees 2013). Evidence for this relates to organisational, system, societal and clinical factors. Specifically: pressure of patient through-put; patient expectations; lack of organisational and social support; increasing isolation - no time to develop teams and communities of practice; and increasingly complex cases and patient co-morbidities. As doctors progress in their career they become increasingly responsible for the coordination of care in response to traumatic events and patient outcomes, while also managing outside pressures. Such factors can lead to an increase in errors (Jackson and Moreton 2013). Errors may be linked to patient diagnosis and treatment, performance of skills and errors in equipment use. Furthermore, the incidence of errors increases along with the amount of sick leave, with the performance of a growing number of doctors attracting scrutiny from the General Medical Council (GMC 2014). The topic of stress management and resilience has therefore attracted a great deal of attention. This ‘How to’ is a guide to strategies that can be used to relieve immediate physiological stress responses and when practised assist in the development of your resilience