Understanding the autophagy-linked disorder BPAN: an integrated approach for studying developmental basis of neurodegenerative diseases

Understanding the fundamental basis of brain disorders is a one of the greatest challenges of the 21st century.

Large-scale genetic studies have identified numerous genes with associated roles in both neurodevelopmental and neurodegenerative disorders, suggesting that common mechanisms are involved in the different phases of the same disease.

Autophagy is such mechanism, which dysfunction during development or in adult can lead to neurodegenerative diseases, including beta-propeller protein-associated neurodegeneration (BPAN).

BPAN is a disease caused by loss-of-function mutations of the autophagy-related gene Wdr45 resulting in neurodevelopmental defects and neurodegenerative phenotypes.

Although BPAN is a rare disease, it represents a genetically simple model to understand the contribution of developmental defects during neurodegenerative disease.

To answer these questions, we will use Drosophila that provides unequaled experimental power for generating models of human neurological diseases and establishing their molecular genetic basis.

Here, using CRISPR/cas9-made Wdr45 null mutant flies generated by Mollereau and col., I examined human Wdr45-linked phenotypes in Drosophila.

I found adult-onset neurodegenerative phenotypes including age-related locomotion decline as well as an abnormal hyperkinetic movements in the embryos of Wdr45 mutants.

Therefore, targeting Wdr45 in Drosophila, we aim not only to allow identifying the developmental and neural basis of autophagy-associated neurodegeneration, but also to uncovering the disease molecular responses that are prior to the appearance of neurodegenerative syndromes.

Ultimately, findings of our proposal can help find early disease biomarkers and design therapies for broad range of neurological disorders.