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Bar-coding neurodegeneration: identifying subcellular effects of human neurodegenerative disease proteins using Drosophila leg neurons.

ABSTRACT: Genetic, biochemical and histological studies have identified a number of different proteins as key drivers of human neurodegenerative diseases. Although different proteins are typically involved in different diseases, there is also considerable overlap. Addressing disease protein dysfunction in an in vivo neuronal context is often time consuming and requires labor-intensive analysis of transgenic models. To facilitate the rapid, cellular analysis of disease protein dysfunction, we have developed a fruit fly (Drosophila melanogaster) adult leg neuron assay. We tested the robustness of 41 transgenic fluorescent reporters and identified a number that were readily detected in the legs and could report on different cellular events. To test these reporters, we expressed a number of human proteins involved in neurodegenerative disease, in both their mutated and wild-type versions, to address the effects on reporter expression and localization. We observed strikingly different effects of the different disease proteins upon the various reporters with, for example, Aβ1-42 being highly neurotoxic, tau, parkin and HTT128Q affecting mitochondrial distribution, integrity or both, and Aβ1-42, tau, HTT128Q and ATX182Q affecting the F-actin network. This study provides proof of concept for using the Drosophila adult leg for inexpensive and rapid analysis of cellular effects of neurodegenerative disease proteins in mature neurons.

SUBMITTER: Fernius J

PROVIDER: S-EPMC5560063 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:The olfactory neuroepithelium is located in the upper vault of the nasal cavity, lying on the olfactory cleft and projecting into the dorsal portion of the superior and middle turbinates beyond the mid-portion of the nasal septum. It is composed of a variety of cell types including olfactory sensory neurons, supporting glial-like cells, microvillar cells, and basal stem cells. The cells of the neuroepithelium are often intermingled with respiratory and metaplastic epithelial cells. Olfactory neurons undergo a constant self-renewal in the timespan of 2-3 months; they are directly exposed to the external environment, and thus they are vulnerable to physical and chemical injuries. The latter might induce metabolic perturbations and ultimately be the cause of cell death. However, the lifespan of olfactory neurons is biologically programmed, and for this reason, these cells have an accelerated metabolic cycle leading to an irreversible apoptosis. These characteristics make these cells suitable for research related to nerve cell degeneration and aging. Recent studies have shown that a non-invasive and painless olfactory brushing procedure allows an efficient sampling from the olfactory neuroepithelium. This approach allows to detect the pathologic prion protein in patients with sporadic Creutzfeldt-Jakob disease, using the real-time quaking-induced conversion assay. Investigating the expression of all the proteins associated to neurodegeneration in the cells of the olfactory mucosa is a novel approach toward understanding the pathogenesis of human neurodegenerative diseases. Our aim was to investigate the expression of α-synuclein, β-amyloid, tau, and TDP-43 in the olfactory neurons of normal subjects. We showed that these proteins that are involved in neurodegenerative diseases are expressed in olfactory neurons. These findings raise the question on whether a relationship exists between the mechanisms of protein aggregation that occur in the olfactory bulb during the early stage of the neurodegenerative process and the protein misfolding occurring in the olfactory neuroepithelium.

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Bar-coding neurodegeneration: identifying subcellular effects of human neurodegenerative disease proteins using Drosophila leg neurons.

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