Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins

In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanudeotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS, but the mechanism of pathogenesis is largely unknown with both gain- and loss-of-function mechanisms being proposed. To better understand C9ORF72-ALS pathogenesis, we generated isogenic induced pluripotent stem cells. MNs with HRE in C9ORF72 showed decreased axonal trafficking compared with gene corrected MNs. However, knocking out C9ORF72 did not recapitulate these changes in MNs from healthy controls, suggesting a gain-of-function mechanism. In contrast, knocking out C9ORF72 in MNs with HRE exacerbated axonal trafficking defects and increased apoptosis as well as decreased levels of HSP70 and HSP40, and inhibition of HSPs exacerbated ALS phenotypes in MNs with HRE. Therefore, we propose that the HRE in C9ORF72 induces ALS pathogenesis via a combination of gain- and loss-of-function mechanisms

Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization

Chorea-acanthocytosis (ChAc) is a fatal neurological disorder characterized by red blood cell acanthocytes and striatal neurodegeneration. Recently, severe cell membrane disturbances based on depolymerized cortical actin and an elevated Lyn kinase activity in erythrocytes from ChAc patients were identified. How this contributes to the mechanism of neurodegeneration is still unknown. To gain insight into the pathophysiology, we established a ChAc patient-derived induced pluripotent stem cell model and an efficient differentiation protocol providing a large population of human striatal medium spiny neurons (MSNs), the main target of neurodegeneration in ChAc. Patient-derived MSNs displayed enhanced neurite outgrowth and ramification, whereas synaptic density was similar to controls. Electrophysiological analysis revealed a pathologically elevated synaptic activity in ChAc MSNs. Treatment with the F-actin stabilizer phallacidin or the Src kinase inhibitor PP2 resulted in the significant reduction of disinhibited synaptic currents to healthy control levels, suggesting a Src kinase- and actin-dependent mechanism. This was underlined by increased G/F-actin ratios and elevated Lyn kinase activity in patient-derived MSNs. These data indicate that F-actin stabilization and Src kinase inhibition represent potential therapeutic targets in ChAc that may restore neuronal function

Construction of meaningful identities in the context of rheumatoid arthritis, motherhood and paid work: A meta-ethnography

Aims and objectives: To derive new conceptual understanding about how women with rheumatoid arthritis manage their illness, motherhood and paid work, based on a comprehensive overview of existing knowledge, gained from qualitative studies. Background: Rheumatoid arthritis affects several social aspects of life; however, little is known about how women with rheumatoid arthritis simultaneously manage their illness, motherhood and paid work. Design: Qualitative metasynthesis. Methods: A qualitative metasynthesis informed by Noblit and Hare's meta-ethnography was carried out, based on studies identified by a systematic search in nine databases. Results: Six studies were included. Social interactions in the performance of three interdependent subidentities emerged as an overarching category, with three subcategories: subidentities associated with (1) paid work, (2) motherhood and (3) rheumatoid arthritis. Pressure in managing one of the subidentities could restrict the fulfilment of the others. The subidentities were interpreted as being flexible, situational, contextual and competing. The women strove to construct meaningful subidentities by taking into account feedback obtained in social interactions. Conclusions: The subidentities associated with paid work and motherhood are competing subidentities. Paid work is given the highest priority, followed by motherhood and illness is the least attractive subidentity. Because of the fluctuating nature of the illness, the women constantly reconstruct the three interdependent subidentities. Relevance to clinical practice: When healthcare professionals meet a woman with rheumatoid arthritis, they should consider that she might not accept the subidentity as an ill person. Health professionals should not expect that women will prioritise their illness in their everyday life. This could be included in clinical conversation with the women.</p