‘Non-self’ & organelle quality control mutations
Explore a project in ‘Non-self’ and organelle quality control mutations: late-onset neurodegeneration is an auto-inflammatory disease.
Neurodegenerative diseases comprise an array of progressive neurological disorders allcharacterised by the selective death of neurons in the central nervous system.
Although, rare (familial) and common (sporadic) forms can occur for the same disease, it is unclear whether this reflects several distinct pathogenic pathways or the convergence of different causes into a common form of nerve cell death.
Remarkably, neurodegenerative diseases are increasingly found to be accompanied by activation of the innate immune surveillance system normally associated with pathogen recognition and response.
Innate surveillance is the cell’s quality control system for the purpose of detecting such danger signals and responding in an appropriate manner. Innate surveillance is an “intelligent system,” in that the manner of response is relevant to the magnitude and duration of the threat.
If possible, the threat is dealt with within the cell in which it is detected, by degrading the danger signal(s) and restoring homeostasis. If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighbouring cells, and recruiting specialised cell types to the site.
If the danger signal persists, then the ultimate response can include not only the programmed death of the original cell, but the contents of this dead cell can also bring about the death of adjacent sensitised cells.
These responses are clearly aimed at destroying the ability of the detected pathogen to propagate and spread. Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes.
Recent studies have revealed how multiple steps in these processes involve proteins that, through their mutation, have been linked to many familial forms of neurodegenerative disease. This suggests that individuals harbouring these mutations may have an amplified response to innate-mediated damage in neural tissues, and renders innate surveillance mediated cell death a plausible common pathogenic pathway responsible for neurodegenerative diseases, in both familial and sporadic forms.
We have assembled evidence in favour of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental danger or damage associated molecular patterns in a progressively expanding cascade of inflammation, tissue damage and cell death. (Richards et al.,2016).
In our Drosophila model (Lawlor et al., 2011; Samaraweera et al., 2013; Richards et al., 2015), endogenously expressed expanded repeat RNA is recognised as ‘non-self’ (like viral RNA) by pattern recognition receptors resulting in innate-mediated nerve cell death.
We are using this model to identify common links in this pathogenic pathway, shared by otherwise distinct neurodegenerative diseases. The honours project will be part of this approach.