scholarly journals Diphenyl diselenide protects a Caenorhabditis elegans model for Huntington's disease by activation of the antioxidant pathway and a decrease in protein aggregation

Metallomics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1142-1158
Author(s):  
Fabiane Bicca Obetine Baptista ◽  
Leticia Priscilla Arantes ◽  
Marina Lopes Machado ◽  
Aline Franzen da Silva ◽  
Larissa Marafiga Cordeiro ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Misfolding ◽  
Nuclear Translocation ◽  
Oxygen Species ◽  
Diphenyl Diselenide ◽  
Disease Treatment ◽  
C Elegans ◽  
Superoxide Dismutase 3 ◽  
Protein Misfolding And Aggregation

The effect of (PhSe)2 in a C. elegans model for Huntington's disease. Treatment with (PhSe)2 triggered the nuclear translocation and activation of DAF-16 transcription factor in C. elegans, inducing the expression of superoxide dismutase-3 (SOD-3) and heat shock protein-16.2 (HSP-16.2). SOD-3 acts on reactive oxygen species (ROS) detoxification, and HSP-16.2 decreases protein misfolding and aggregation, which occur in HD.

A drug candidate for Alzheimer’s and Huntington’s disease, PBT2, can be repurposed to render Neisseria gonorrhoeae susceptible to natural cationic antimicrobial peptides

2021 ◽  
Author(s):  
Freda E -C Jen ◽  
Ibrahim M El-Deeb ◽  
Yaramah M Zalucki ◽  
Jennifer L Edwards ◽  
Mark J Walker ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Antimicrobial Peptides ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Proteomic Analysis ◽  
Protein Misfolding ◽  
Membrane Integrity ◽  
Drug Candidate ◽  
Cationic Antimicrobial Peptides ◽  
Broth Microdilution Method

Abstract Background Neisseria gonorrhoeae is a Gram-negative bacterial pathogen that causes gonorrhoea. No vaccine is available to prevent gonorrhoea and the emergence of MDR N. gonorrhoeae strains represents an immediate public health threat. Objectives To evaluate whether PBT2/zinc may sensitize MDR N. gonorrhoeae to natural cationic antimicrobial peptides. Methods MDR strains that contain differing resistance mechanisms against numerous antibiotics were tested in MIC assays. MIC assays were performed using the broth microdilution method according to CLSI guidelines in a microtitre plate. Serially diluted LL-37 or PG-1 was tested in combination with a sub-inhibitory concentration of PBT2/zinc. Serially diluted tetracycline was also tested with sub-inhibitory concentrations of PBT2/zinc and LL-37. SWATH-MS proteomic analysis of N. gonorrhoeae treated with PBT2/zinc, LL-37 and/or tetracycline was performed to determine the mechanism(s) of N. gonorrhoeae susceptibility to antibiotics and peptides. Results Sub-inhibitory concentrations of LL-37 and PBT2/zinc synergized to render strain WHO-Z susceptible to tetracycline, whereas the killing effect of PG-1 and PBT2/zinc was additive. SWATH-MS proteomic analysis suggested that PBT2/zinc most likely leads to a loss of membrane integrity and increased protein misfolding and, in turn, results in bacterial death. Conclusions Here we show that PBT2, a candidate Alzheimer’s and Huntington’s disease drug, can be repurposed to render MDR N. gonorrhoeae more susceptible to the endogenous antimicrobial peptides LL-37 and PG-1. In the presence of LL-37, PBT2/zinc can synergize with tetracycline to restore tetracycline susceptibility to gonococci resistant to this antibiotic.

Nuclear translocation of AMPK-a1 potentiates striatal neurodegeneration in Huntington's disease

2011 ◽  
Vol 208 (8) ◽  
pp. i24-i24 ◽  
Author(s):  
Tz-Chuen Ju ◽  
Hui-Mei Chen ◽  
Jiun-Tsai Lin ◽  
Ching-Pang Chang ◽  
Wei-Cheng Chang ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Nuclear Translocation

scholarly journals SREBP2 delivery to striatal astrocytes normalizes transcription of cholesterol biosynthesis genes and ameliorates pathological features in Huntington’s Disease

2020 ◽  
Author(s):  
Giulia Birolini ◽  
Gianluca Verlengia ◽  
Francesca Talpo ◽  
Claudia Maniezzi ◽  
Lorena Zentilin ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Nuclear Translocation ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Biosynthesis Pathway ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Cholesterol Biosynthesis Pathway

AbstractBrain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington’s Disease (HD). One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP-controlled genes in the cholesterol biosynthesis pathway.Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the N-terminal fragment of human SREBP2 (hSREBP2).Robust hSREBP2 expression in striatal glial cells in HD mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversed Drd2 transcript levels decline, cleared muHTT aggregates and attenuated behavioral deficits. We conclude that glial SREBP2 participates in HD brain pathogenesis in vivo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of HD.

scholarly journals A comparative meta-analysis of membraneless organelle associated proteins with age related proteome of C. elegans

2021 ◽  
Author(s):  
Pritam Mukherjee ◽  
Prajnadipta Panda ◽  
Prasad Kasturi
Keyword(s):  
Protein Misfolding ◽  
Meta Analysis ◽  
Adverse Conditions ◽  
C Elegans ◽  
Age Related ◽  
Associated Proteins ◽  
Altered Metabolism ◽  
Protein Misfolding And Aggregation ◽  
Cellular Components ◽  
Liquid Condensate

Proteome imbalance can lead to protein misfolding and aggregation which is associated with pathologies. Protein aggregation can also be an active, organized process and can be exploited by cells as a survival strategy. In adverse conditions, it is beneficial to deposit the proteins in a condensate rather degrading and resynthesizing. Membrane less organelles (MLOs) are biological condensates formed through liquid liquid phase separation (LLPS), involving cellular components such as nucleic acids and proteins. LLPS is a regulated process, which when perturbed, can undergo a transition from a physiological liquid condensate to pathological solid-like protein aggregates. To understand how the MLO-associated proteins (MLO-APs) behave during aging, we performed a comparative meta analysis with age related proteome of C. elegans. We found that the MLO-APs are highly abundant throughout the lifespan. Interestingly, they are aggregating more in long-lived mutant worms compared to the age matched wildtype worms. GO term analysis revealed that the cell cycle and embryonic development are among the top enriched processes in addition to RNA metabolism RNP components. Considering antagonistic pleotropic nature of these developmental genes and post mitotic status of C. elegans, we assume that these proteins phase transit during post development. As the organism ages, these MLO-APs either mature to become more insoluble or dissolve in uncontrolled manner. However, in the long-lived daf-2 mutant worms, the MLOs may attain protective states due to enhanced proteostasis components and altered metabolism that eventually make these worms more protected.

scholarly journals Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington’s disease treatment

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Alejandro Lopez-Hurtado ◽  
Diego A. Peraza ◽  
Pilar Cercos ◽  
Laura Lagartera ◽  
Paz Gonzalez ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Small Molecules ◽  
Huntington’S Disease ◽  
Calcium Sensor ◽  
Disease Treatment ◽  
Neuronal Calcium Sensor
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