Modeling diseases of aging in larval zebrafish, a paradoxical yet powerful strategy

Neurodegenerative diseases are a set of devastating medical conditions in which neuronal loss associated with the aggregation of toxic proteins leads to progressive cognitive impairment. These diseases are usually modeled in animals by mimicking late disease stages through genetic modifications that aggressively accumulate proteins that damage the brain. However, these diseases typically unfold over decades, and disease-associated genes are known to have important, but understudied, biological functions in early life stages. To address this research gap, we suggest that the larval zebrafish, which has conserved orthologs of most neurodegeneration-linked genes, is an excellent model to examine early mechanisms that set the stage for disease progression, such as altered neuronal function, synaptic re-wiring, and proteostasis. We propose a systematic genetic modeling and phenotyping pipeline in zebrafish that integrates CRISPR editing, high-throughput behavioral assays, brain-wide activity mapping, and pharmacological screens to capture neurodegenerative disease-related changes that occur well before clinical disease emerges. Studying diseases of aging in larval zebrafish may sound paradoxical; however, by uncovering cellular dysfunction at the earliest stages of disease in a living vertebrate brain, this approach could identify critical therapeutic targets at timepoints before degeneration becomes irreversible.