Tauopathies are a diverse group of neurodegenerative diseases characterized by the accumulation of hyperphosphorylated tau protein, which significantly impacts neuronal health and is associated with cognitive decline and movement disorders. Among these, progressive supranuclear palsy (PSP) stands out as a well-characterized 4-repeat tauopathy, involving the aggregation of tau isoforms with four microtubule-binding domains. Despite advancements in genetic research, the specific genetic variants contributing to PSP, particularly in diverse populations, remain poorly understood.

Our project aims to address the critical knowledge gap regarding primary 4-repeat tauopathies in Lebanon, where no prevalence studies or genetic data currently exist. We intend to identify genetic variants associated with PSP in the Lebanese population through whole exome sequencing (WES). Genetic screening is focusing on known disease-related genes to identify both established and novel pathogenic variants linked to PSP, thereby enhancing our understanding of the genetic factors involved. Concurrently, we are creating neuronal cell models using CRISPR-Cas9 technology to validate the identified mutations and explore their functional implications. We are also generating humanized zebrafish transgenic models to assess the impact of these mutations on phenotype and behavior, hypothesizing that these models will exhibit identifiable phenotypic changes and reduced lifespan due to the overexpression of human 4-repeat tau.

By investigating PSP in the Lebanese population, this study seeks to uncover unique clinical characteristics associated with the disease, expanding knowledge beyond predominantly European ancestries. Our findings will lay the groundwork for future studies on the pathophysiological mechanisms of tauopathies and provide preclinical models for evaluating personalized treatment strategies, ultimately benefiting Lebanese patients and the broader scientific community.

Further information about PSP:

International Parkinson and Movement Disorder Society (MDS)
www.movementdisorders.org/ 

CurePSP (USA)
https://www.psp.org/

PSP Association (UK)
https://www.pspassociation.org.uk/ 

The Coleen Cunningham Foundation (CCF) for PSP awareness 
https://pspawareness.com/