Identifying common molecular mechanisms underlying polyQ related diseases

PolyQ diseases are a group of diseases which share a common feature – a deleterious repetition of glutamine in specific proteins, and similar pathological characteristics, such as neuronal defects, expansion of polyQ repeats with each passing generation and late onset.

In attempting to elucidate the molecular mechanisms underlying the common polyQ diseases phenotype, I use in my research, a set of exclusive cell lines, which have great potential to shed new light on the subject. In this work, I employ two cell models of polyQ diseases; Huntington`s disease and Machado-Joseph Disease, as representatives of the neurodegenerative polyQ group. Each disease model includes both cells from patients, which were reprogramed into induced Pluripotent Stem Cells (iPSCs), as well as Embryonic Stem Cells (ESCs), derived from human embryos of preimplantation genetic diagnosis (PGD). In addition, all mutated cell lines (iPSCs and ESCs) are isogenically CRISPR/Cas9 corrected, generating two WT alleles in the same genetic background.

I use these unique research tools in order to identify early general common effects of polyQ. I focus on three time points of differentiation: Pluripotency, Neuronal identity and 3D differentiation into mini-brain organoids. In each time point I perform several large scale analyses to characterize the epigenetic and chromatin states as well as gene expression profiles.

This work aspires to find common features of the polyQ disorders, rather than focusing on a specific disease. This will help clarify the general polyQ effects as a whole, which will contribute to understanding these diseases.