Neural Regen Res. 2025 Jan 01. 20(1): 21-28
Rare neurological diseases, while individually are rare, collectively impact millions globally, leading to diverse and often severe neurological symptoms. Often attributed to genetic mutations that disrupt protein function or structure, understanding their genetic basis is crucial for accurate diagnosis and targeted therapies. To investigate the underlying pathogenesis of these conditions, researchers often use non-mammalian model organisms, such as Drosophila (fruit flies), which is valued for their genetic manipulability, cost-efficiency, and preservation of genes and biological functions across evolutionary time. Genetic tools available in Drosophila, including CRISPR-Cas9, offer a means to manipulate gene expression, allowing for a deep exploration of the genetic underpinnings of rare neurological diseases. Drosophila boasts a versatile genetic toolkit, rapid generation turnover, and ease of large-scale experimentation, making it an invaluable resource for identifying potential drug candidates. Researchers can expose flies carrying disease-associated mutations to various compounds, rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and, ultimately, clinical trials. In this comprehensive review, we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis, pathophysiology, and potential therapeutic implications. We discuss rare diseases associated with both neuron-expressed and glial-expressed genes. Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay, mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay, and mutations in IRF2BPL causing seizures, a neurodevelopmental disorder with regression, loss of speech, and abnormal movements. And we explore mutations in EMC1 related to cerebellar atrophy, visual impairment, psychomotor retardation, and gain-of-function mutations in ACOX1 causing Mitchell syndrome. Loss-of-function mutations in ACOX1 result in ACOX1 deficiency, characterized by very-long-chain fatty acid accumulation and glial degeneration. Notably, this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology, offering a platform for the rapid identification of potential therapeutic interventions. Rare neurological diseases involve a wide range of expression systems, and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia. Furthermore, mutations within the same gene may result in varying functional outcomes, such as complete loss of function, partial loss of function, or gain-of-function mutations. The phenotypes observed in patients can differ significantly, underscoring the complexity of these conditions. In conclusion, Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases. By facilitating the modeling of these conditions, Drosophila contributes to a deeper understanding of their genetic basis, pathophysiology, and potential therapies. This approach accelerates the discovery of promising drug candidates, ultimately benefiting patients affected by these complex and understudied diseases.