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TP53INP1 is a stress-induced protein, which acts as a dual positive regulator of transcription and of autophagy and whose deficiency has been linked with cancer and metabolic syndrome. Here, we addressed the unexplored role of TP53INP1 and of its  Drosophila  homolog dDOR in the maintenance of neuronal homeostasis under chronic stress, focusing on dopamine (DA) neurons under normal ageing- and Parkinson’s disease (PD)-related context.  Trp53inp1  − / −  mice displayed additional loss of DA neurons in the substantia nigra compared to wild-type (WT) mice, both with ageing and in a PD model based on targeted overexpression of α-synuclein. Nigral  Trp53inp1  expression of WT mice was not significantly modified with ageing but was markedly increased in the PD model.  Trp53inp2  expression showed similar evolution and did not differ between WT and  Trp53inp1  − / −  mice. In  Drosophila , pan-neuronal  dDOR  overexpression improved survival under paraquat exposure and mitigated the progressive locomotor decline and the loss of DA neurons caused by the human α-synuclein A30P variant.  dDOR  overexpression in DA neurons also rescued the locomotor deficit in flies with RNAi-induced downregulation of  dPINK1  or  dParkin . Live imaging, confocal and electron microscopy in fat bodies, neurons, and indirect flight muscles showed that  dDOR  acts as a positive regulator of basal autophagy and mitophagy independently of the PINK1-mediated pathway. Analyses in a mammalian cell model confirmed that modulating  TP53INP1  levels does not impact mitochondrial stress-induced PINK1/Parkin-dependent mitophagy. These data provide the first evidence for a neuroprotective role of TP53INP1/dDOR and highlight its involvement in the regulation of autophagy and mitophagy in neurons.

TP53INP1 exerts neuroprotection under ageing and Parkinson’s disease-related stress condition