SUMMARY Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S tau mice. Reducing TIA1 decreases the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibits the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles (NFTs). Despite the increase in NFTs, TIA1 reduction increases neuronal survival and rescues behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity, and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a paradigm in which dysfunction of the translational stress response leads to tau-mediated pathology.

Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.

Neuroinflammation is indicated in the pathogenesis of several acute and chronic neurological disorders. Acute lesions in the brain parenchyma induce intense and highly complex neuroinflammatory reactions with similar mechanisms among various disease prototypes. Microglial cells in the CNS sense tissue damage and initiate inflammatory responses. The cellular and humoral constituents of the neuroinflammatory reaction to brain injury contribute significantly to secondary brain damage and neurodegeneration. Inflammatory cascades such as proinflammatory cytokines from invading leukocytes and direct cell-mediated cytotoxicity between lymphocytes and neurons are known to cause "collateral damage" in models of acute brain injury. In addition to degeneration and neuronal cell loss, there are secondary inflammatory mechanisms that modulate neuronal activity and affect neuroinflammation which can even be detected at the behavioral level. Hence, several of health conditions result from these pathogenetic conditions which are underlined by progressive neuronal function loss due to chronic inflammation and oxidative stress. In the first part of this Review, we discuss critical neuroinflammatory mediators and their pathways in detail. In the second part, we review the phytochemicals which are considered as potential therapeutic molecules for treating neurodegenerative diseases with an inflammatory component.

Nanoparticle synthesis is an important area of nanotechnology and has been performed by undergraduate students frpm various universities across the globe. Due to the availability of massive data on the synthesis of a wide variety of metallic nanoparticles, including silver, gold, selenium, zinc, copper, iron, palladium, platinum, titanium, etc., and their oxides, it has become tedious to select an ideal and workable protocol for their synthesis. Herein, we have focused on the standardized chemical and biological methodologies to prepare selenium nanoparticles (SeNPs or nanoselenium). Chemical methods exploit chemicals such as sodium selenite (Na 2 SeO 3 ) and reductants (L-ascorbic acid, glutathione, etc.), along with stabilizing agents (Polysorbate 20, protic acid, lysozyme). Although these methods have been used for commercial purposes, they suffer from several drawbacks such as the use of excessive additives for controlled morphology, multistep synthesis, high running cost, and environmental toxicity. Biogenic synthesis using plant materials and microorganisms (algae, fungi, yeast, bacteria, and viruses), on the other hand, is a sustainable, environment-friendly, and cost-effective approach. The natural reducing agents facilitate the conversion of selenium salts into nanosized selenium particles in a single step and act as capping and stabilizing agents, which impart synergism in biological activities. Physical methods such as hydrothermal, irradiation, pulsed laser ablation, etc., have also been used for their production; however, high cost, stringent conditions, and high energy consumption have hampered their applications. Herein, we present a step-by-step methodology using chemical and biological reducing agents to synthesize selenium nanoparticles which will assist the undergraduate learners in selecting a well-tested method based on the conditions of an experiment and desired applications.