Nguyen, Y. T. N. | bioRxiv Science

bioRxiv2022

MYXOBACTERIA FROM VIETNAM: ISOLATION, PHYLOGENETIC ANALYSIS AND BIOPROSPECTION

Forty-three myxobacterial strains were isolated and identified from 20 soil samples collected in Vietnam. The information on morphological characteristics and 16S ribosomal gene sequencing showed that these strains were designated to seven genera belonging to Angiococcus, Archangium, Chondromyces, Corallococcus, Cystobacter, Melittangium, and Myxococcus, in suborder Cystobacterineae and Sorangiineae. The phylogenetic tree was constructed to clarify the genetic relationship between myxobacterial isolates. Myxobacteria were cultured, and crude extracts were obtained after 10-day fermentation in P-medium in the presence of the Amberlite XAD 16N adsorbent resin. Elution was carried out with acetone and methanol to obtain the crude extracts. Evaluation of antioxidant activity used the DPPH and ABTS assay, the minimum inhibitory concentration values were determined by the microdilution method. The total extract from CT21 had the highest total antioxidant activity (IC50 = 52.34 {+/-} 1.47 {micro}g/mL, 30.28 {+/-} 0.74 {micro}g/mL for DPPH and ABTS assays, respectively). The other potential strain was TG131 and GL41 that IC50 values were 40.28 {+/-} 1.13 and 57.24 {+/-} 1.52 {micro}g/mL, respectively (by the DPPH method), and 48.35 {+/-} 0.58 and 42.76 {+/-} 0.50 {micro}g/mL, respectively (by the ABTS method). Interestingly, 100% isolated myxobacterial strains show inhibitory activity against at least one of the tested microorganisms. The potential antimicrobial strain was GL41, which inhibited all tested microorganisms, and the MIC values were 1 {micro}g/mL against MRSA, MSSA, S. faecalis, C. albicans, and A. niger. The highest active strains were members of Myxococcus sp. genus.

microbiology↗

bioRxiv2021

Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulate. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that aging further reduces HTT palmitoylation. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons. HighlightsO_LIPalmitoylation of mHTT is reduced in multiple transgenic HD mouse models C_LIO_LIHTT palmitoylation decreases with increasing polyQ length in HD patient cells C_LIO_LImHTT-lowering in mouse brains does not rescue aberrant palmitoylation C_LIO_LImHTT palmitoylation in HD patient-derived cells can be rescued via APT inhibition C_LIO_LIPromoting palmitoylation reduces mHTT aggregation and cytotoxicity in vitro C_LI

neuroscience↗