Investigation into the role of PATL1 gene in neurodevelopment using Drosophila melanogaster as model organism

Neurodevelopmental disorders (NDDs) comprise a wide spectrum of conditions characterized by limited cognitive, emotional, and motor abilities. To understand the genetic causes of NDDs and examine underlying biological pathways, the fruit fly Drosophila melanogaster serves as an ideal model, allowing for screening of candidate genes with straightforward analyses. Recently, a variant in the human PATL1 gene was identified in a patient with walking difficulties and intellectual disability, suggesting that PATL1 is a candidate gene for NDDs (Sezer, unpublished). In this thesis, I aimed to determine the neurodevelopmental consequences of variations in the PATL1 gene via functional, morphological, and behavioral analyses by manipulating its fruit fly ortholog; Hpat gene. I show that Hpat mutations as well as ubiquitous downregulation of Hpat result in larval lethality, while pan-neuronal downregulation of Hpat causes partial lethality accompanied by severe motor dysfunction. Behavioral analyses revealed that the motor defects had early onset, with downregulation of Hpat both in muscles and neurons impairing larval locomotion and turning behavior. Additionally, I show that Hpat is necessary for the development of the mushroom body in the fly brain–the learning and memory center–and that Hpat plays a critical role in the laminar organization of the ellipsoid body, the fly's counterpart to the basal ganglia. Finally, to model the human disease-causing PATL1[K518fs] variant, I generated transgenic flies expressing PATL1 and PATL1[K518fs]. The findings in this thesis emphasize the critical role of Hpat in neurodevelopment and proves Drosophila useful for modeling PATL1-linked NDDs.