Unraveling molecular signaling in neurodegenerative diseases:focus on a protective mechanism mediated by linalool

Neurodegenerative conditions such as Alzheimer`s disease (AD) and stroke are characterized by progressive nervous system dysfunction. The main aim of this work was to propose new therapeutic targets in neurodegeneration and to identify possible phospholipid biomarkers that reflect the progression of the disease. We demonstrated that administration of the terpene, linalool was able to reduce the main pathological markers of AD (extracellular β-amyloidosis, tauopathy) and of ischemic stroke. Linalool treatment in animals improved motor coordination and cognition, along with a reduction of astrogliosis and microgliosis in the hippocampus. Besides, we investigated whether and how linalool exert a neuroprotective effect against glutamate-induced oxidative stress and might affect mitochondrial function. Administration of linalool reduced cell death mediated by glutamate, mitochondrial ROS formation, mitochondrial calcium uptake, lipid peroxidation and mediated a recovery of mitochondrial membrane potential, together with an increase in mitochondrial respiration. In addition, we detected remarkable changes in phospholipids in ischemic stroke, AD and CADASIL in brain samples, CSF and serum. These data could help to unravel novel molecular mechanisms and propose different therapeutic targets to treat transversal pathogenesis. Finally, we showed in a review the role of microglia in neurodegenerative diseases and we present the results of a differentiation protocol of human microglia from iPSC demonstrating the maturity and functionality of these cells. In conclusion, we present various strategies to model and study neurodegeneration and provide answers in the field of inflammation, lipidomics and at the same time we propose a new molecule as a potential therapy against AD and cerebral ischemia

The multifaceted role of LRRK2 in Parkinson's disease:From human iPSC to organoids

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting elderly people. Pathogenic mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are the most common cause of autosomal dominant PD. LRRK2 activity is enhanced in both familial and idiopathic PD, thereby studies on LRRK2-related PD research are essential for understanding PD pathology. Finding an appropriate model to mimic PD pathology is crucial for revealing the molecular mechanisms underlying disease progression, and aiding drug discovery. In the last few years, the use of human-induced pluripotent stem cells (hiPSCs) grew exponentially, especially in studying neurodegenerative diseases like PD, where working with brain neurons and glial cells was mainly possible using postmortem samples. In this review, we will discuss the use of hiPSCs as a model for PD pathology and research on the LRRK2 function in both neuronal and immune cells, together with reviewing the recent advances in 3D organoid models and microfluidics

Identification and Characterization of a Small Molecule that Activates Thiosulfate Sulfurtransferase and Stimulates Mitochondrial Respiration

The enzyme Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), is a positive genetic predictor of diabetes type 2 and obesity. As increased TST activity protects against the development of diabetic symptoms in mice, an activating compound for TST may provide therapeutic benefits in diabetes and obesity. We identified a small molecule activator of human TST through screening of an inhouse small molecule library. Kinetic studies in vitro suggest that two distinct isomers of the compound are required for full activation as well as an allosteric mode of activation. Additionally, we studied the effect of TST protein and the activator on TST activity through mitochondrial respiration. Molecular docking and molecular dynamics (MD) approaches supports an allosteric site for the binding of the activator, which is supported by the lack of activation in the E. coli. mercaptopyruvate sulfurtransferase. Finally, we show that increasing TST activity in isolated mitochondria increases mitochondrial oxygen consumption. This article is protected by copyright. All rights reserved.</p