Thesis
French
ID: <
10670/1.xcomr6>
Abstract
The stress-induced protein TP53INP1 acts as a dual positive regulator of transcription and of autophagy. Its deficiency has been linked with cancer and metabolic syndrome via mechanisms common to those involved in neurodegenerative diseases, including altered autophagy, oxidative stress and chronic inflammation. In this work, we investigated the unexplored role of TP53INP1 in the maintenance of neuronal homeostasis under chronic stress. We focused on the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) whose degeneration is the main neuropathological hallmark of Parkinson’s disease (PD) and which are also preferentially vulnerable to degeneration during normal ageing. We performed comparative regional analysis of DA neuron loss and behavioral testing in WT and Trp53inp1-KO mice at different ages and at different time points of the degenerative process in a progressive PD model based on viral vector-mediated overexpression of human α-synuclein. Results show that the ageing-related DA neurodegeneration, which is restricted to the anterior part of the SNc in WT mice, extended to the posterior SNc in Trp53inp1-KO mice. In the PD model, TP53INP1 deficiency globally aggravates the progressive DA neurodegeneration and associated motor deficits. In both conditions, the calbindin-expressing dopamine subpopulation showed higher vulnerability to TP53INP1 deficiency than the one expressing aldehyde dehydrogenase 1a1. These data provide the first evidence for a neuroprotective role of TP53INP1 and emphasize the heterogeneity of responses to cellular stress among DA neurons.