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Reductions in brain kynurenic acid levels, a neuroinhibitory metabolite, improve cognitive function in diverse organisms. Thus, modulation of kynurenic acid levels is thought to have therapeutic potential in a range of brain disorders. Here we report that the steroid 5-androstene 3β, 17β-diol (ADIOL) reduces kynurenic acid levels and promotes associative learning in Caenorhabditis elegans We identify the molecular mechanisms through which ADIOL links peripheral metabolic pathways to neural mechanisms of learning capacity. Moreover, we show that in aged animals, which normally experience rapid cognitive decline, ADIOL improves learning capacity. The molecular mechanisms that underlie the biosynthesis of ADIOL as well as those through which it promotes kynurenic acid reduction are conserved in mammals. Thus, rather than a minor intermediate in the production of sex steroids, ADIOL is an endogenous hormone that potently regulates learning capacity by causing reductions in neural kynurenic acid levels.

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age- and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

Mutations in the microtubule-associated protein tau (MAPT) underlie multiple neurodegenerative disorders, yet the pathophysiological mechanisms are unclear. A novel variant in MAPT resulting in an alanine to threonine substitution at position 152 (A152T tau) has recently been described as a significant risk factor for both frontotemporal lobar degeneration and Alzheimer's disease. Here we use complementary computational, biochemical, molecular, genetic and imaging approaches in Caenorhabditis elegans and mouse models to interrogate the effects of the A152T variant on tau function. In silico analysis suggests that a threonine at position 152 of tau confers a new phosphorylation site. This finding is borne out by mass spectrometric survey of A152T tau phosphorylation in C. elegans and mouse. Optical pulse-chase experiments of Dendra2-tau demonstrate that A152T tau and phosphomimetic A152E tau exhibit increased diffusion kinetics and the ability to traverse across the axon initial segment more efficiently than wild-type (WT) tau. A C. elegans model of tauopathy reveals that A152T and A152E tau confer patterns of developmental toxicity distinct from WT tau, likely due to differential effects on retrograde axonal transport. These data support a role for phosphorylation of the variant threonine in A152T tau toxicity and suggest a mechanism involving impaired retrograde axonal transport contributing to human neurodegenerative disease.

A general feature of animal aging is decline in learning and memory. Here we show that in Caenorhabditis elegans, a significant portion of this decline is due to accumulation of kynurenic acid (KYNA), an endogenous antagonist of neural N-methyl-D-aspartate receptors (NMDARs). We show that activation of a specific pair of interneurons either through genetic means or by depletion of KYNA significantly improves learning capacity in aged animals even when the intervention is applied in aging animals. KYNA depletion also improves memory. We show that insulin signaling is one factor in KYNA accumulation.

In species ranging from humans to Caenorhabditis elegans, dietary restriction (DR) grants numerous benefits, including enhanced learning. The precise mechanisms by which DR engenders benefits on processes related to learning remain poorly understood. As a result, it is unclear whether the learning benefits of DR are due to myriad improvements in mechanisms that collectively confer improved cellular health and extension of organismal lifespan or due to specific neural mechanisms. Using an associative learning paradigm in C. elegans, we investigated the effects of DR as well as manipulations of insulin, mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and autophagy pathways-processes implicated in longevity-on learning. Despite their effects on a vast number of molecular effectors, we found that the beneficial effects on learning elicited by each of these manipulations are fully dependent on depletion of kynurenic acid (KYNA), a neuroinhibitory metabolite. KYNA depletion then leads, in an N-methyl D-aspartate receptor (NMDAR)-dependent manner, to activation of a specific pair of interneurons with a critical role in learning. Thus, fluctuations in KYNA levels emerge as a previously unidentified molecular mechanism linking longevity and metabolic pathways to neural mechanisms of learning. Importantly, KYNA levels did not alter lifespan in any of the conditions tested. As such, the beneficial effects of DR on learning can be attributed to changes in a nutritionally sensitive metabolite with neuromodulatory activity rather than indirect or secondary consequences of improved health and extended longevity.

Accidental or suicidal poisoning with yellow phosphorus or metal phosphides (YPMP) such as aluminum (AlP) zinc phosphide (Zn 3 P 2) commonly causes acute liver failure (ALF) and cardiotoxicity. These are used as household, agricultural, and industrial rodenticides and in production of ammunitions, firecrackers, and fertilizers. In absence of a clinically available laboratory test for diagnosis or toxin measurement or an antidote, managing their poisoning is challenging even at a tertiary-care center with a dedicated liver intensive care unit (LICU) and liver transplant facility. Patients with YPMP-related ALF were monitored using standardized clinical, hemodynamic, biochemical, metabolic, neurological, electrocardiography (ECG), and sequential organ failure assessment (SOFA) score and managed using uniform intensive care, treatment, and transplant protocols in LICU. Sociodemographic characteristics, clinical and biochemical parameters, and scores were summarized and compared between 3 groups i.e. spontaneous survivors, transplanted patients, and non-survivors. Predictors of spontaneous survival and the need for liver transplant are also evaluated. Nineteen patients with YPMP-related ALF were about 32 years old (63.2% females) and presented to us at a median of 3 (0–10) days after poisoning. YPMP-related cardiotoxicity was rapidly progressive and fatal, whereas liver transplant was therapeutic for ALF. Spontaneous survivors had lower-dose ingestion (<17.5 g), absence of cardiotoxicity, < grade 3 hepatic encephalopathy (HE), lactate < 5.8, SOFA score < 14.5, and increase in SOFA score by < 5.5. Patients with renal failure need for continuous veno-venous hemodiafiltration (CVVHDF) and King College criteria positivity on account of prothrombin time and international normalized ratio (PT-INR) > 6.5 had higher mortality risk. Patients undergoing liver transplant and with spontaneous recovery required longer intensive care unit and hospital stay. At median follow-up of 3.4 (2.6–5.5) years, all spontaneous survivors and transplanted patients are well with normal liver function. Early transfer to a specialized center, preemptive close monitoring, and intensive care and organ support with ventilation, CVVHDF, plasmapheresis, and others may maximize their chances of spontaneous recovery, allowing accurate prognostication and a timely liver transplant. [ABSTRACT FROM AUTHOR]