Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

Highlights d Nesprin-2 recruits microtubule motors, but not actin, for neuronal migration d BicD2 mediates dynein and kinesin-1 binding to Nesprin-2 d Kinesin-1 opposes the forward forces exerted by dynein d Nuclear and centrosome transport are largely independent in neurons Authors Joã o Carlos Gonç alves,

Quercetin, a prominent dietary antioxidant present in vegetables, especially onions, fruits, highlighting apples and berries, wine and tea, belongs to a group of plant derived heterocyclic polyphenols. These compounds could be important mediators of the biological actions attributed to healthy diets. Chemically, quercetin is a type of flavonoid that specifically belongs to the flavonols group. It naturally occurs either as glycoside or aglycone, both of which have biological activity. Many of the natural sources of quercetin are included in the Mediterranean diet, a dietary habit associated with a decrease of cardiovascular diseases. During the last years, several researches have reported effects consistent with pharmacological applications of quercetin in cardiovascular diseases, such as atherosclerosis, ischemia-reperfusion injury, cardiotoxicity, and hypertension, among others. In this review, the pathways and molecules involved in the beneficial effects of quercetin are summarized. In addition, a scope of the new insights concerning quercetin pharmacokinetics, pharmacodynamics and bioavailability are presented. The mechanisms whereby quercetin exerts its effects have not been fully elucidated. However, interesting results have been obtained from early clinical studies involving cardioprotection by quercetin, but much knowledge is still lacking in the field of its bioavailability to improve the clinical application of this flavonol. This study presents evidence supporting the point of view that quercetin should be considered a potential therapeutic agent against cardiovascular diseases, giving rise to novel applications in their prevention and treatment.

Highlights d Rab-interacting lysosomal protein (RILP) binds ATG5, LC3, Rab7, and cytoplasmic dynein d RILP controls autophagosome (AP) biogenesis, retrograde transport, and p62 turnover d RILP expression and function are controlled by mTOR kinase d ATG5-dynein competition for RILP coordinates AP biogenesis with transport

words)Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD, and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endo-lysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery.Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAVmediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

The human retrovirus human T cell lymphotropic virus type-I (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Axonal degeneration in HAM/TSP patients occurs without neuron infection, with the secreted viral Tax protein proposed to be involved. We previously found that Tax secreted into the culture medium of MT-2 cells (HTLV-1-infected cell line) produced neurite retraction in neuroblastoma cells differentiated to neuronal type. To assess the relevance of Tax posttranslational modifications on this effect, we addressed the question of whether Tax secreted by MT-2 cells and peripheral blood mononuclear cells (PBMCs) of HTLV-1-infected subjects is modified. The interaction of Tax with calreticulin (CRT) that modulates intracellular Tax localization and secretion has been described. We studied Tax localization and modifications in MT-2 cells and its interaction with CRT. Intracellular Tax in MT-2 cells was assessed by flow cytometry, corresponding mainly to a 71-kDa protein followed by western blot. This protein reported as a chimera with gp21 viral protein-confirmed by mass spectrometry-showed no ubiquitination or SUMOylation. The Tax-CRT interaction was determined by confocal microscopy and coimmunoprecipitation. Extracellular Tax from HAM/TSP PBMCs is ubiquitinated according to western blot, and its interaction with CRT was shown by coimmunoprecipitation. A positive correlation between Tax and CRT secretion was observed in HAM/TSP PBMCs and asymptomatic carriers. For both proteins inhibitors and activators of secretion showed secretion through the endoplasmic reticulum-Golgi complex. Tax, present in PBMC culture medium, produced neurite retraction in differentiated neuroblastoma cells. These results suggest that Tax, whether ubiquitinated or not, is active for neurite retraction.

Semaphorins are secreted and transmembrane proteins that bind plexin/ neuropilin or integrin receptors, providing paracrine axonal guidance signals and ultimately leading to a functional and developed neuronal network. Following semaphorin's initial discovery, their relevance in the central nervous system (CNS) soon intrigued researchers about the possible links between semaphorins, their receptors and signaling mechanisms and different neurodegenerative diseases. Here, we explore the current knowledge of semaphorin's function and signaling in Alzheimer's disease (AD), Parkinson's disease (PD), Charcot-Marie-Tooth disease (CMT), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We focus on the effects of the most known semaphorin subclasses 3A and 4D, yet extending our discussion to other semaphorins that have been found involved in specific neuropathologies and the potential effect of semaphorins modulating the immune system in disorders with inflammatory components. Molecular, cellular, and genetic evidences are reviewed, highlighting the relevance of semaphorins on each disease etiology, pathophysiology, and progression. The newly discovered semaphorin functions in neurological disorders even suggest alternative therapies that may be highly valuable in diseases that have no current cure.

Human lymphotropic virus type 1 (HTLV-1) is a retrovirus causing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurodegenerative central nervous system (CNS) axonopathy. This virus mainly infects CD4 + T lymphocytes without evidence of neuronal infection. Viral Tax, secreted from infected lymphocytes infiltrated in the CNS, is proposed to alter intracellular pathways related to axonal cytoskeleton dynamics, producing neurological damage. Previous reports showed a higher proteolytic release of soluble Semaphorin 4D (sSEMA-4D) from CD4 + T cells infected with HTLV-1. Soluble SEMA-4D binds to its receptor Plexin-B1, activating axonal growth collapse pathways in the CNS. In the current study, an increase was found in both SEMA-4D in CD4+ T cells and sSEMA-4D released to the culture medium of peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients compared to asymptomatic carriers and healthy donors. After a 16-h culture, infected PBMCs showed significantly higher levels of CRMP-2 phosphorylated at Ser 522 . The effect was blocked either with anti-Tax or anti-SEMA-4D antibodies. The interaction of Tax and sSEMA-4D was found in secreted medium of PBMCs in patients, which might be associated with a leading role of Tax with the SEMA-4D-Plexin-B1 signaling pathway. In infected PBMCs, the migratory response after transwell assay showed that sSEMA-4D responding cells were CD4 + Tax + T cells with a high CRMP-2 pSer 522 content. In the present study, the participation of Tax-sSEMA-4D in the reduction in neurite growth in PC12 cells produced by MT2 (HTLV-1-infected cell line) culture medium was observed. These results lead to the participation of plexins in the reported effects of infected lymphocytes on neuronal cells.