Machine learning discriminates a movement disorder in a zebrafish model of Parkinson's disease

Abstract

Animal models of human disease provide an in vivo system that can reveal molecular mechanisms by which mutations cause pathology, and, moreover, have the potential to provide a valuable tool for drug development. Here we have developed a zebrafish model of Parkinson's disease (PD) together with a novel method to screen for movement disorders in adult fish, pioneering a more efficient drug testing route. Mutation of the PARK7 gene (DJ-1) is known to cause monogenic autosomal recessive PD in humans and, using CRISPR/Cas9 gene editing we have generated a DJ-1 loss of function zebrafish with molecular hallmarks of PD. To establish whether there is a human-relevant parkinsonian phenotype in our model, we have adapted proven tools used to diagnose PD in clinics and have developed a novel and unbiased computational method to classify movement disorders in adult zebrafish. Using high-resolution video capture and machine learning, we have extracted novel features of movement from continuous data streams and used an evolutionary algorithm (EA) to classify parkinsonian fish. This method will be widely applicable for assessing zebrafish models of human motor diseases and provide a valuable asset for the therapeutics pipeline. In addition, interrogation of RNA-seq data indicate metabolic reprogramming of brains in the absence of DJ-1, adding to growing evidence that disruption of bioenergetics is a key feature of neurodegeneration.

Artificial intelligence and machine learning‐aided drug discovery in central nervous system diseases: State‐of‐the‐arts and future directions

“…Monzel et al 406 created a human midbrain organoid model of PD as an in vitro toxicity assay and built an RF classifier to predict compounds' neurotoxic effect on organoids based on cellular features. To establish an efficient drug‐testing route, Hughes et al 407 developed a zebrafish model of PD together with an AI/ML‐based method to classify movement disorders in this model using high‐resolution video captures. Encouraging results of all the studies discussed above, highlight the potential benefits of AI/ML applications for the discovery of efficient and multitargeting drugs against emerging targets in PD as well as the screening of the drug effects on PD models.…”

Differential effects of loss ofpark7activity on Iron Responsive Element (IRE) gene sets: Implications for the role of iron dyshomeostasis in the pathophysiology of Parkinson’s disease

“…We would like to acknowledge the senior author of the paper (8), Mary Elizabeth Pownall for making available the raw transcripts data, and Nhi Hin for providing the sets of zebrafish genes containing iron-responsive elements.…”

“…RNA-seq was performed on whole brains from 4-month-old park7 −/− zebrafish (compared to wild type), and gene set enrichment analysis (GSEA) was used to predict cellular processes altered by loss of park7 function. Gene set enrichment profiles were observed consistent with disrupted metabolism and upregulation of genes associated with oxidative phosphorylation (8). We hypothesized that oxidative stress and/or iron dyshomeostasis in park7 −/− zebrafish brains would alter binding of IRPs to transcripts containing IREs, thereby altering transcript stability.…”

“…Orthologues of PD genes have previously been identified and manipulated in zebrafish. For example, Hughes et al (8) developed a novel zebrafish model to examine the function of PARK7. RNA-seq was performed on whole brains from 4-month-old park7 −/− zebrafish (compared to wild type), and gene set enrichment analysis (GSEA) was used to predict cellular processes altered by loss of park7 function.…”

First person – Gideon Hughes

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Gideon Hughes is first author on ‘ Machine learning discriminates a movement disorder in a zebrafish model of Parkinson's disease ’, published in DMM. Gideon conducted the research described in this article while a PhD student in Betsy Pownall's lab at the University of York, York, UK.…”