Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS.

Electrocatalytic NO reduction reaction to generate NH 3 under ambient conditions offers an attractive alternative to the energy-extensive Haber-Bosch route; however, the challenge still lies in the development of cost-effective and high-performance electrocatalysts. Herein, nanoporous VN film is first designed as a highly selective and stable electrocatalyst for catalyzing reduction of NO to NH 3 with a maximal Faradaic efficiency of 85% and a peak yield rate of 1.05 × 10 -7 mol•cm -2 •s -1 (corresponding to 5,140.8 g•h -1 •mg cat.-1 ) at -0.6 V vs. reversible hydrogen electrode in acid medium. Meanwhile, this catalyst maintains an excellent activity with negligible current density and NH 3 yield rate decays over 40 h. Moreover, as a proof-of-concept of Zn-NO battery, it delivers a high power density of 2.0 mW•cm -2 and a large NH 3 yield rate of 0.22 × 10 -7 mol•cm -2 •s -1 (corresponding to 1,077.1 g•h -1 •mg cat.-1 ), both of which are comparable to the best-reported results. Theoretical analyses confirm that the VN surface favors the activation and hydrogenation of NO by suppressing the hydrogen evolution. This work highlights that the electrochemical NO reduction is an eco-friendly and energy-efficient strategy to produce NH 3 .

Neuroinflammation is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS), but only limited data are available on systematic peripheral and central immune cell profiles in ALS. We studied detailed immune profiles of 73 ALS patients and 48 healthy controls (controls) in peripheral blood by fluorescence-activated cell sorting as well as cytokine expression profiles in serum. In a subgroup of 16 ALS patients and 10 controls we additionally studied cerebrospinal fluid (CSF) samples. In peripheral blood, T cell subtypes presented a shift towards pro-inflammatory Th 1 and Th 17 cells whereas anti-inflammatory Th2 and T regulatory cells were decreased. Important players in innate immunity including distinct monocyte (Mo) and natural killer (NK) cell subtypes were changed in ALS patients compared to controls. Pro-inflammatory serum cytokines such as interleukin (IL)-1 beta, IL-6 and interferon-gamma (IFN-gamma) were increased and the anti-inflammatory cytokine IL-10 was decreased. Correlation analysis revealed moderate negative correlations between Th1 and Th17 to the ALS functional rating scale revised (ALSFRS-R) and to forced vital capacity. In CSF samples, no relevant alteration of the immune profile was found. In conclusion, the immune profile in ALS was shifted towards a Th1/Th17 cell-mediated pro-inflammatory immune response and correlated to disease severity and progression. Large prospective studies are needed to confirm these findings. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which affects the upper and lower motoneurons (MN) leading to progressive muscle weakness, paralysis and ultimately death due to respiratory failure. The pathophysiological mechanisms are still unresolved, although increasing knowledge gained in the last two decades. Multiple studies corroborated that numerous pathological processes are involved in MN degeneration and neuroinflammation gained increasing attention and had deemed as a pathological hallmark of ALS 1-3. It is commonly accepted that the non-neuronal neighbors play a significant role in the degenerative process of this vulnerable cell type 4. One of the most impressive pathohistological characteristics during disease progression is activation and increase abundance of microglial cells in the central nervous system (CNS) shown in animal models of ALS 5 as well as in human studies 6-8. Microglial cells are considered to be the resident mononuclear phagocytes in the CNS and can be renewed by bone marrow cells under special circumstances 9,10. It is supposable that specialized peripheral immune cell subsets are attracted to the central compartment to contribute and perpetuate the pathological processes in ALS disease by local inflammation or activation of resident cells. Therefore, neuroinflammation is not limited to the CNS, it needs a systemic inflammatory response to enable the local inflammation. In general, a systemic inflammatory response is very complex, a plethora of different immune cells are involved, diverse cytokines a...

Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson’s disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker (iNOS/NO, IL-1β, and IL-6) expression and reduction of M2 marker (Arginase1, Ym1/2, and IL-10) were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α. Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated when Atg5 knockdown in BV2 cells but alleviated when microglia pretreatment with rapamycin. Activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation as the AKT specific inhibitor perifosine prevented the increase of LC3II (an autophagic marker) in TNF-α stimulated microglia. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.