Dottorato in BIOCHIMICA

Titolo della tesi: Deciphering the interplay between the Unfolded Protein Response and metabolic defects in Down syndrome neuropathology

A maladaptive response, such as chronic activation of the unfolded protein response (UPR), links the accumulation of misfolded proteins, increased oxidative damage, and neurotoxicity. We recently reported that dysregulation of the PERK branch of the UPR is associated with reduced Nrf2 antioxidant response, contributing to the progression of Alzheimer-like signatures in the Down syndrome (DS) brain. Additionally, our studies support the notion that, in the DS brain, insulin resistance (BIR) and mitochondrial defects advance in parallel to faulty proteostasis, resulting in redox imbalance and cognitive decline. However, within this context, it is important to consider that one of the major challenges in studying DS is the lack of reliable murine models that accurately replicate the genotypic and phenotypic aspects observed in humans during aging. Preclinical studies in DS have been pioneered using the Ts65Dn murine model, which carries the triplication of about 90 coding genes orthologous to chromosome 21 (HSA21), as well as non-orthologous coding genes that limit the model's ability to mimic the consequences of genetic overdosage in DS. Based on this premise, we decided to investigate a new murine model, Ts66Yah, generated by CRISPR/Cas9 to exclude the genomic region unrelated to HSA21 from the minichromosome, thereby enhancing the model's validity in studying DS. Once consolidated the alterations of several pathways whose roles have been ascribed to the neurodegeneration and intellectual disability in Ts66Yah, we plan to shift to in vitro models analysis with the purpose of detailing the molecular mechanisms underlying the chronicity of DS phenotype in developing defects in proteostasis under aberrant metabolic stimuli. This enables us to unravel the role of trisomic genes in exacerbating the toxic partnership between BIR and UPR. Data collected so far in Ts66Yah provide novel and consolidated insights, devoid of genome bias, concerning trisomy-driven processes that contribute to brain pathology in association with ageing. Meanwhile, our results also assess that metabolic defects occurring in DS exacerbate the failure in the PERK pathway regulation and they are both cause and effect of NRF2 signal depletion, representing an essential step in promoting aberrant proteostasis and neurodegeneration.