An In Vivo Model of Alpha-Synuclein Spread from Gut to Brain
Background: Parkinson's disease is a progressive neurodegenerative disorder characterized by the presence of pathological aggregation of the protein alpha-synuclein and the loss of dopaminergic neurons in the substantia nigra. There is evidence that misfolding and propagation of alpha-synuclein aggregates through networks of interconnected neurons is responsible for the pathological spread and progress neuron loss. However, in vivo models demonstrating such pathological progression remain elusive. Results: This study utilizes a zebrafish model in order to interrogate the mechanisms of alpha- synuclein toxicity and spread. We describe the development of a zebrafish model of endogenous neuronal human alpha-synuclein expression that causes, in young fish, behavioral and neuronal changes as well as microglia activation. In aged fish, alpha-synuclein expression induces a slow but progressive pathological phenotype manifesting in neuron loss within the gut and the CNS. This model is further utilized to seed gut pathology by incorporating a novel method of feeding human alpha-synuclein preformed fibrils in order to initiate protein misfolding at an early age. The combination of endogenous neuronal expression of alpha-synuclein and the exogenous addition of misfolded protein facilitates the development of brain pathology and subsequent neuron loss in the CNS. In addition to the pathological alterations induced with the fibril feeding model, genetic changes were identified by single cell RNA sequencing. These gene changes resulted in pathway alteration that implicate neurodegenerative disease processes. Conclusion: This model of alpha-synuclein pathology is useful for understanding mechanisms underlying disease initiation and can replicate the progressive development of pathological synuclein accumulation. It has the potential to induce neuron to neuron spread and also offers a way to explore what interventions may prevent such pathological progression.