Study of the role of parkin transcriptional function in neuroplasticity and memory formation in Alzheimer's disease – AlzParking

The etiological trigger of Alzheimer’s disease (AD) remains to be identified. Among various hypothesis, the amyloid cascade has been widely studied but outcomes of clinical trials centered around the amyloid peptide have been disappointing. Our project stands outside this mainstream view. We postulate that parkin (PK), a protein linked to Parkinson’s pathology, could participate in the control of several key physiological processes, namely neural plasticity and memory formation and that PK dysfunction could account for memory defects occurring in AD.
PK was described as a E3-ubiquitin-ligase. However, we were first to establish that PK also behaves as a transcription factor (TF). We have designed molecular tools enabling us to definitely delineate the respective contribution of E3-ligase and TF functions of parkin in a given phenotype. Supporting our postulate, we previously showed that PK controls XBP1S, a TF involved in the control of memory formation. Importantly, we recently gathered RNAseq transcriptomic data comparing control (PK+) and PK invalidated (PK-) mice whole brain samples and demonstrated the regulation of key synaptic activity-inducible immediate early genes, some of which were reported to be altered concomitantly to AD cognitive decline.
In this project, we aim at determining 1) the specific contribution of PK TF and/or E3-ligase functions in the control of neuroplasticity ex-vivo; 2) the molecular mechanisms underlying the impact of PK TF on the modulation of synaptic activity-inducible immediate early genes; 3) the impact of PK and selected transcriptional targets in the control of neuroplasticity in AD-like animal models and 4) the evaluation of the PK-linked neuroplasticity targets in human AD sporadic iPScs and fibroblasts.
At the end of the project, we should be able to establish the respective contribution of E3-ligase and TF function of PK on the control of neuroplasticity and memory formation and how this could be altered in AD condition.