Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3

Repeat expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts in C9orf72 are translated into five dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Furthermore, we found that hnRNPA3 is depleted from the nucleus and partially mislocalized to cytoplasmic poly-GA inclusions in C9orf72 patients, suggesting that poly-GA sequesters hnRNPA3 within the cytoplasm. We now demonstrate that hnRNPA3 also binds to the antisense repeat RNA. Both DPR production and deposition from sense and antisense RNA repeats are increased upon hnRNPA3 reduction. All DPRs induced DNA double strand breaks (DSB), which was further enhanced upon reduction of hnRNPA3. Poly-glycine-arginine and poly-proline-arginine increased foci formed by phosphorylated Ataxia Telangiectasia Mutated (pATM), a major sensor of DSBs, whereas poly-glycine-alanine (poly-GA) evoked a reduction of pATM foci. In dentate gyri of C9orf72 patients, lower nuclear hnRNPA3 levels were associated with increased DNA damage. Moreover, enhanced poly-GA deposition correlated with reduced pATM foci. Since cytoplasmic pATM deposits partially colocalized with poly-GA deposits, these results suggest that poly-GA, the most frequent DPR observed in C9orf72 patients, differentially causes DNA damage and that poly-GA selectively sequesters pATM in the cytoplasm inhibiting its recruitment to sites of DNA damage. Thus, mislocalization of nuclear hnRNPA3 caused by poly-GA leads to increased poly-GA production, which partially depletes pATM, and consequently enhances DSB

Orf - an orphan disease?

Human orf should be considered based on a typical presentation with erythematous papule/nodule to avoid unnecessary over-treatment

Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)? : A post-mortem study of 80 ALS patients

Background: Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown. Objective: To investigate the effect of NIV and PEG on survival and causes of death in ALS patients. Methods: Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015. Forty-two of these patients consented for genetic testing. Effects of NIV and PEG on survival and causes of death were analyzed in a multivariable Cox proportional hazard regression. Results: Six patients, who requested assisted suicide causing drug-induced hypoxia, were excluded from final analysis. Respiratory failure was the main cause of death in 72 out of 74 patients. Fifteen out of 74 died of aspiration pneumonia 23/74 of bronchopneumonia and 8/74 of a combination of aspiration pneumonia and bronchopneumonia. Twenty died of hypoxia without concomitant infection, and six patients had pulmonary embolism alone or in combination with pneumonia. NIV (p = 0.01) and PEG (p<0.01) had a significant impact on survival. In patients using NIV bronchopneumonia was significantly more frequent (p <0.04) compared to non-NIV patients. This effect was even more pronounced in limb onset patients (p<0.002). Patients with C9orf72 hexanucleotide repeat expansions showed faster disease progression and shorter survival (p = 0.01). Conclusion: The use of NIV and PEG prolongs survival in ALS. This study supports current AAN and EFNS guidelines which recommend NIV and PEG as a treatment option in ALS. The risk of bronchopneumonia as cause of death may be increased by NIV

Evaluation of Two 3D Printers for Guided Implant Surgery

To compare the suitability of a fused filament fabrication (FFF) consumer 3D printer with a professional digital light processing (DLP) printer for the production of surgical templates for guided oral implant surgery.; Eight virtual templates were printed with two different 3D printers. These were optically scanned and the incongruences between virtual and printed templates were determined after alignment of the surface scans and the virtual data. Minimum, maximum, and mean incongruences were determined, and a t test between both groups was performed to determine statistically significant differences in accuracy.; Templates printed with the professional DLP printer showed statistically significantly less incongruence (P = .001) than those fabricated by the consumer FFF 3D printer.; The accuracy of manufactured templates is strongly dependent on the printing device and method. At this time, the tested consumer 3D FFF printer is not suitable for the fabrication of templates for implant guided surgery. Minimum requirements regarding printers' features and 3D-printed templates need to be assessed in future studies

Characteristic of the autopsy cohort.

<p>Characteristic of the autopsy cohort.</p

Risk of bronchopneumonia under NIV.

<p>Risk of bronchopneumonia under NIV.</p

Autopsy confirmed causes of death in %.

<p>Autopsy confirmed causes of death in %.</p

Impact of NIV and PEG on survival^*.

<p>Impact of NIV and PEG on survival^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0177555#t002fn002" target="_blank">*</a>}.</p

Brca1 is expressed in human microglia and is dysregulated in human and animal model of ALS

International audienceBackground : There is growing evidence that microglia are key players in the pathological process of amyotrophiclateral sclerosis (ALS). It is suggested that microglia have a dual role in motoneurone degeneration through therelease of both neuroprotective and neurotoxic factors.Results : To identify candidate genes that may be involved in ALS pathology we have analysed at early symptomaticage (P90), the molecular signature of microglia from the lumbar region of the spinal cord of hSOD1G93Amice, the mostwidely used animal model of ALS. We first identified unique hSOD1G93Amicroglia transcriptomic profile that, in additionto more classical processes such as chemotaxis and immune response, pointed toward the potential involvement of thetumour suppressor gene breast cancer susceptibility gene 1(Brca1). Secondly, comparison with our previous data onhSOD1G93Amotoneurone gene profile substantiated the putative contribution of Brca1 in ALS. Finally, we establishedthat Brca1 protein is specifically expressed in human spinal microglia and is up-regulated in ALS patients.Conclusions : Overall, our data provide new insights into the pathogenic concept of a non-cell-autonomous disease andthe involvement of microglia in ALS. Importantly, the identification of Brca1 as a novel microglial marker and as possiblecontributor in both human and animal model of ALS may represent a valid therapeutic target. Moreover, our data pointstoward novel research strategies such as investigating the role of oncogenic proteins in neurodegenerative diseases