Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder of the central nervous system (CNS) that is defined by a CAG expansion in exon 1 of the huntingtin gene leading to the production of mutant huntingtin (mHtt). To date, the disease pathophysiology has been thought to be primarily driven by cell-autonomous mechanisms, but, here, we demonstrate that fibroblasts derived from HD patients carrying either 72, 143 and 180 CAG repeats as well as induced pluripotent stem cells (iPSCs) also characterized by 143 CAG repeats can transmit protein aggregates to genetically unrelated and healthy host tissue following implantation into the cerebral ventricles of neonatal mice in a non-cell-autonomous fashion. Transmitted mHtt aggregates gave rise to both motor and cognitive impairments, loss of striatal medium spiny neurons, increased inflammation and gliosis in associated brain regions, thereby recapitulating the behavioural and pathological phenotypes which characterizes HD. In addition, both in vitro work using co-cultures of mouse neural stem cells with 143 CAG fibroblasts and the SH-SY5Y human neuroblastoma cell line as well as in vivo experiments conducted in newborn wild-type mice suggest that exosomes can cargo mHtt between cells triggering the manifestation of HD-related behaviour and pathology. This is the first evidence of human-to-mouse prion-like propagation of mHtt in the mammalian brain; a finding which will help unravel the molecular bases of HD pathology as well as to lead to the development of a whole new range of therapies for neurodegenerative diseases of the CNS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1582-9) contains supplementary material, which is available to authorized users.
This study introduces a cellulose nanofiber surfactant system, in which the surface is hydrophobically modified with different alkyl chain structures for the effective envelopment of solid lipid microparticles (SLMs). To endow bacterial cellulose nanofibers (BCNFs) with excellent ability to assemble at the lipid-water interface, alkyl chains with designated molecular structures, such as decane, didecane, and eicosane, are covalently grafted onto the BCNF surface. Interfacial tension and interfacial rheology measurements indicate that dialkyl chain-grafted BCNFs (diC 10 BCNF) exhibit strong interfibrillar association at the interface. The formation of a dense and tough fibrillary membrane contributes significantly to the enveloping of the SLMs, regardless of the lipid type. Because the diC 10 BCNF-enveloped SLMs exhibit a core molecular crystalline phase at the microscale, they can immobilize an oil-soluble antioxidant while maintaining its long-term storage stability. These findings show that the cellulose-surfactant-based SLM technology is applicable to the stabilization and formulation of readily denatured active ingredients.
Microfluidics forms the basis of unique experimental approaches that visualize the development of neural structure using micro-scale devices and aids the guidance of neurite growth in an axonal isolation compartment. We utilized microfluidics technology to monitor the differentiation and migration of neural cells derived from human embryonic stems cells (hESC). We cocultured hESC with PA6 stromal cells and isolated neural rosette-like structures, which subsequently formed neurospheres in a suspension culture. We found that Tuj1-positive neural cells but not nestin-positive neural precursor cells (NPC) were able to enter the microfluidics grooves (microchannels), suggesting a neural cell-migratory capacity that was dependent on neuronal differentiation. We also showed that bundles of axons formed and extended into the microchannels.Taken together, these results demonstrated that microfluidics technology can provide useful tools to study neurite outgrowth and axon guidance of neural cells, which are derived from human embryonic stem cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.