Ricerc@Sapienza

A major challenge in neurobiology is identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, also present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2a and antioxidant protein production via induction of the transcription factor Nrf2. In contrast, PERK prolonged activation leads to sustained reduction in protein synthesis and induction of cell death pathways. To further investigate the role of the PERK pathway in neurodegenerative disorders, we focused on Down syndrome (DS), in which aging confers a high risk of Alzheimer-like dementia (AD). Preliminary data investigating human DS frontal cortices and blood derived cells from DS subject suggest an early and sustained activation of PERK associated with the induction of eIF2a and ATF4 downstream signals. We also observed that the Nrf2 response is uncoupled from PERK and its antioxidant effects is repressed in a mechanism implicating the transcription repressor Bach1 (enchoded on chromosome 21).
However, the molecular mechanisms involved are still undetermined. The overall objective of this project is to understand the processes that lead to PERK/NRF2 uncoupling in DS with the idea of identifying compounds able to rescue their physiological interaction and reduce brain damage. The central hypothesis is that trisomy 21 lead to chronic PERK over-activation contributing with BACH1 over-expression, to NRF2 depletion. The reduction of PERK chronic over-activation could allow to the rescue of PERK/NRF2 axis thus re-establishing proper proteostasis and reducing oxidative damage.