The spread of pathological assemblies in neurodegenerative disease

Neurodegenerative diseases represent a significant burden on global health. Their incidence and prevalence are projected to increase dramatically over the next few decades. Yet no effective disease-modifying treatments exist, partly owing to our incomplete understanding of pathogenesis. It is known that neurodegenerative diseases are caused by the misfolding of specific neural proteins. However, it is not fully known how this misfolding results in neuronal dysfunction and death, nor why different diseases preferentially affect different regions of the brain. In recent years, there has been increasing evidence that the direct propagation of misfolded proteins along neural pathways, in a manner reminiscent of misfolded prion protein, is a common principle across many neurodegenerative diseases. In particular, it has been hypothesised that Parkinson’s disease may originate with the misfolding and aggregation of the protein α-synuclein in the enteric nervous system or olfactory bulb, followed by its propagation to the brain, where it causes disease. This may initially be triggered by environmental exposure to agents that induce the misfolding of endogenous α-synuclein in the gut or nose, and is therefore known as the dual-hit hypothesis. However, at the time of our study, this had not been clearly demonstrated experimentally and no causative agent had definitively been identified. Given that misfolded α-synuclein has been shown to be capable of inducing the misfolding of native α-synuclein, we hypothesised that, if the dual-hit hypothesis were true, exposure to aggregated α-synuclein itself in the gut or nose might trigger this pathological pathway, whether or not it is the causative agent in the environment. Here, we prepared pathological forms of α-synuclein and studied its administration into experimental animals via a variety of routes, including oral, nasal, and haematogenous. To achieve an experimentally feasible timeframe, we made use of the hemizygous M83 transgenic mouse model of Parkinson’s disease, which involves overexpression of human mutated α-synuclein but no filamentous assembly or neurodegeneration within most of the normal mouse lifespan. We demonstrate that, in these animals, oral or nasal exposure to aggregated α-synuclein led to severe neurodegeneration. Within several months, affected animals developed significant motor impairment that progressed towards paralysis, with neuropathological deposits of misfolded α-synuclein appearing throughout the neuraxis. These deposits developed in neuroanatomically related regions in a pattern resembling prion neuroinvasion, suggesting that misfolded α-synuclein may propagate along neural pathways. We also show that neuropathology and neurodegenerative disease developed following haematogenous exposure to aggregated α-synuclein, even with minute amounts of exposure, and even with α-synuclein derived from diseased human brain. Our experiments represent one of the first demonstrations, since the discovery of prions, that exposure to a misfolded protein via natural routes of entry can induce neurodegenerative disease. Our findings lend support to the dual-hit hypothesis of Parkinson’s disease, and our experimental paradigms can be utilised as models for the peripheral misfolding and propagation of α-synuclein. Further work remains to be done to identify other potential triggers of α-synuclein misfolding and aggregation in the gut and nose, and to elucidate the precise molecular mechanisms underlying its inter-neuronal propagation. Deciphering the origins of α-synuclein misfolding and its mechanisms of propagation will likely offer important insights into the pathogenesis of Parkinson’s disease and other synucleinopathies, and aid the development of novel diagnostic and therapeutic strategies for these debilitating disorders.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Chen, John

Advisor dc:contributor.advisor

• Goedert, Michel

• Neurology
• Neuroscience

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ff4b053c-d946-48f6-8989-650ef112af35/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.99649

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/353539