Summary Onset of neurodegenerative disorders, including Huntington’s disease, is strongly influenced by aging. Hallmarks of aged cells include compromised nuclear envelope integrity, impaired nucleocytoplasmic transport, and accumulation of DNA double-strand breaks. We show that mutant huntingtin markedly accelerates all of these cellular phenotypes in a dose- and age-dependent manner in cortex and striatum of mice. Huntingtin-linked polyglutamine initially accumulates in nuclei, leading to disruption of nuclear envelope architecture, partial sequestration of factors essential for nucleocytoplasmic transport (Gle1 and RanGAP1), and intranuclear accumulation of mRNA. In aged mice, accumulation of RanGAP1 together with polyglutamine is shifted to perinuclear and cytoplasmic areas. Consistent with findings in mice, marked alterations in nuclear envelope morphology, abnormal localization of RanGAP1, and nuclear accumulation of mRNA were found in cortex of Huntington’s disease patients. Overall, our findings identify polyglutamine-dependent inhibition of nucleocytoplasmic transport and alteration of nuclear integrity as a central component of Huntington’s disease.

SummaryThrough the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs.Video Abstract

Chagas disease is caused by Trypanosoma cruzi infection, being cardiomyopathy the more frequent manifestation. New chemotherapeutic drugs are needed but there are no good biomarkers for monitoring treatment efficacy. There is growing evidence linking immune response and metabolism in inflammatory processes and specifically in Chagas disease. Thus, some metabolites are able to enhance and/or inhibit the immune response. Metabolite levels found in the host during an ongoing infection could provide valuable information on the pathogenesis and/or identify deregulated metabolic pathway that can be potential candidates for treatment and being potential specific biomarkers of the disease. To gain more insight into those aspects in Chagas disease, we performed an unprecedented metabolomic analysis in heart and plasma of mice infected with T. cruzi. Many metabolic pathways were profoundly affected by T. cruzi infection, such as glucose uptake, sorbitol pathway, fatty acid and phospholipid synthesis that were increased in heart tissue but decreased in plasma. Tricarboxylic acid cycle was decreased in heart tissue and plasma whereas reactive oxygen species production and uric acid formation were also deeply increased in infected hearts suggesting a stressful condition in the heart. While specific metabolites allantoin, kynurenine and p-cresol sulfate, resulting from nucleotide, tryptophan and phenylalanine/tyrosine metabolism, respectively, were increased in heart tissue and also in plasma. These results provide new valuable information on the pathogenesis of acute Chagas disease, unravel several new metabolic pathways susceptible of clinical management and identify metabolites useful as potential specific biomarkers for monitoring treatment and clinical severity in patients.

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