Breakdown of the Central Synapses in C9orf72-Linked ALS/FTD

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease that leads to the death of motor and cortical neurons. The clinical manifestations of ALS are heterogenous, and efficacious treatments to significantly slow the progression of the disease are lacking. Cortical hyper-excitability is observed pre-symptomatically across disease-causative genetic variants, as well as in the early stages of sporadic ALS, and typically precedes motor neuron involvement and overt neurodegeneration. The causes of cortical hyper-excitability are not yet fully understood but is mainly agreed to be an early event. The identification of the nucleotide repeat expansion (GGGGCC)n in the C9ORF72 gene has provided evidence that ALS and another neurodegenerative disease, frontotemporal dementia (FTD), are part of a disease spectrum with common genetic origins. ALS and FTD are diseases in which synaptic dysfunction is reported throughout disease onset and stages of progression. It has become apparent that ALS/FTD-causative genes, such as C9ORF72, may have roles in maintaining the normal physiology of the synapse, as mutations in these genes often manifest in synaptic dysfunction. Here we review the dysfunctions of the central nervous system synapses associated with the nucleotide repeat expansion in C9ORF72 observed in patients, organismal, and cellular models of ALS and FTD

A multidomain hub anchors the chromosome segregation and chemotactic machinery to the bacterial pole

The cell poles constitute key subcellular domains that are often critical for motility, chemotaxis, and chromosome segregation in rod-shaped bacteria. However, in nearly all rods, the processes that underlie the formation, recognition, and perpetuation of the polar domains are largely unknown. Here, in Vibrio cholerae, we identified HubP (hub of the pole), a polar transmembrane protein conserved in all vibrios, that anchors three ParA-like ATPases to the cell poles and, through them, controls polar localization of the chromosome origin, the chemotactic machinery, and the flagellum. In the absence of HubP, oriCI is not targeted to the cell poles, chemotaxis is impaired, and a small but increased fraction of cells produces multiple, rather than single, flagella. Distinct cytoplasmic domains within HubP are required for polar targeting of the three ATPases, while a periplasmic portion of HubP is required for its localization. HubP partially relocalizes from the poles to the mid-cell prior to cell division, thereby enabling perpetuation of the polar domain in future daughter cells. Thus, a single polar hub is instrumental for establishing polar identity and organization

A mouse model with widespread expression of the C9orf72-linked glycine-arginine dipeptide displays non-lethal ALS/FTD-like phenotypes

Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes in these mice, including mild motor neuron loss, but no TDP-43 mis-localization, as well as motor and cognitive impairments. We suggest that this model can serve as the foundation for phenotypic exacerbation through second-hit forms of stress

Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS/FTD

Aberrant hexanucleotide repeat expansions in C9orf72 are the most common genetic change underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA transcripts containing these expansions undergo repeat-associated non-ATG translation (RAN-T) to form five dipeptide repeat proteins (DPRs). DPRs are found as aggregates throughout the CNS of C9orf72-ALS/FTD patients, and some cause degeneration when expressed in vitro in neuronal cultures and in vivo in animal models. The spread of characteristic disease-related proteins drives the progression of pathology in many neurodegenerative diseases. While DPR toxic mechanisms continue to be investigated, the potential for DPRs to spread has yet to be determined. Using different experimental cell culture platforms, including spinal motor neurons derived from induced pluripotent stem cells from C9orf72-ALS patients, we found evidence for cell-to-cell spreading of DPRs via exosome-dependent and exosome-independent pathways, which may be relevant to disease

Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ALS/FTD is rescued by SV2 replenishment

Abstract The most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an intronic hexanucleotide repeat expansion in the C9orf72 gene. In disease, RNA transcripts containing this expanded region undergo repeat‐associated non‐AUG translation to produce dipeptide repeat proteins (DPRs), which are detected in brain and spinal cord of patients and are neurotoxic both in vitro and in vivo paradigms. We reveal here a novel pathogenic mechanism for the most abundantly detected DPR in ALS/FTD autopsy tissues, poly‐glycine‐alanine (GA). Previously, we showed motor dysfunction in a GA mouse model without loss of motor neurons. Here, we demonstrate that mobile GA aggregates are present within neurites, evoke a reduction in synaptic vesicle‐associated protein 2 (SV2), and alter Ca2+ influx and synaptic vesicle release. These phenotypes could be corrected by restoring SV2 levels. In GA mice, loss of SV2 was observed without reduction of motor neuron number. Notably, reduction in SV2 was seen in cortical and motor neurons derived from patient induced pluripotent stem cell lines, suggesting synaptic alterations also occur in patients

Reallocating time to sleep, sedentary, and active behaviours in non-Hodgkin lymphoma survivors: associations with patient-reported outcomes

The purpose of this study was to examine potential effects of reallocating time between sleep, sedentary and active behaviours on fatigue symptoms and quality of life in a sample of non-Hodgkin lymphoma survivors. Non-Hodgkin lymphoma survivors identified from the Western Australian Cancer Registry (N = 149) (response rate = 36%; median age = 64 years) wore an Actigraph® GT3X+ accelerometer for 7 days and completed the Fatigue Scale, the Functional Assessment of Cancer Therapy-General and the Pittsburgh Sleep Quality Index. We used isotemporal substitution methods in linear regression models to examine the potential effects of reallocating time between sleep, sedentary and activity behaviours on fatigue and quality of life. Data collection was conducted in Western Australia in 2013. Significant differences were observed for fatigue symptoms when 30 min per day of bouted moderate-to-vigorous physical activity (10 min) was reallocated from 30 min per day of sleep (5.7 points, 95% CI = 1.8, 9.7), sedentary time bouts (20 min) (5.7 points, 95% CI = 1.6, 9.7), sedentary time non-bouts (5.1 points, 95% CI = 1.0, 9.3) or light intensity activity (5.5 points, 95% CI = 1.5, 9.5). Isotemporal substitution effects of reallocating sedentary time, sleep and light physical activity with bouted physical activity was significantly associated with fatigue, but not quality of life. Findings from the present study may aid in the development and delivery of health behaviour interventions that are more likely to influence the health outcome of interest