No abstract

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS’ tendency to aggregate is normally buffered by interacting RBPs, but this buffering is lost when FUS mislocalizes to the cytoplasm due to ALS mutations. The presence of aggregation-prone FUS in the cytoplasm causes imbalances in RBP homeostasis that exacerbate neurodegeneration. However, enhancing autophagy using small molecules reduces cytoplasmic FUS, restores RBP homeostasis and rescues motor function in vivo. We conclude that disruption of RBP homeostasis plays a critical role in FUS-ALS and can be treated by stimulating autophagy. Electronic supplementary material The online version of this article (10.1007/s00401-019-01998-x) contains supplementary material, which is available to authorized users.

The ethanol, methanol and acetone extracts of Aloe vera gel were studied for their antimicrobial activity against four Gram-positive and Gram-negative bacteria using agar well diffusion method. The extracts showed varied levels of antimicrobial activity against the tested pathogens. The ethanol and methanol extracts showed higher activity while acetone extract, showed least or no activity against most of the tested pathogens. Fractions obtained from the extracts by Thin Layer and Column Chromatography were studied for their antagonistic properties using Spot Assay Technique. Compounds with maximum antibacterial activity isolated from the ethanol and methanol extracts were identified as p -coumaric acid (Mol. wt.165), ascorbic acid (Mol. wt.177 ), pyrocatechol (Mol. wt.110 ) and cinnamic acid (Mol.wt.148), on the basis of Gas Chromatography Mass Spectrometry. The study suggests the antimicrobial activity of the A. vera gel extract to be dependant on the synergistic effect of different compounds. With the broad spectral antimicrobial effect of A. vera gel, it could be further recommended in the treatment of various bacterial diseases.

Amyloid-β (Aβ) associates with extracellular vesicles termed exosomes. It is not clear whether and how exosomes modulate Aβ neurotoxicity in Alzheimer's disease (AD). We show here that brain tissue and serum from the transgenic mouse model of familial AD (5xFAD) and serum from AD patients contains ceramide-enriched and astrocyte-derived exosomes (termed astrosomes) that are associated with Aβ. In Neuro-2a cells, primary cultured neurons, and human induced pluripotent stem cell-derived neurons, Aβ-associated astrosomes from 5xFAD mice and AD patient serum were specifically transported to mitochondria, induced mitochondrial clustering, and upregulated the fission protein Drp-1 at a concentration corresponding to 5 femtomoles Aβ/L of medium. Aβassociated astrosomes, but not wild type or control human serum exosomes, mediated binding of Aβ to voltagedependent anion channel 1 (VDAC1) and subsequently, activated caspases. Aβ-associated astrosomes induced neurite fragmentation and neuronal cell death, suggesting that association with astrosomes substantially enhances Aβ neurotoxicity in AD and may comprise a novel target for therapy.