TP53INP1 exerts neuroprotection under ageing and Parkinson\u2019s disease-related stress condition

Emilie Dinh,Noemi Asfogo,Thomas Rival,Christophe Melon,Lydia Kerkerian-Le Goff,Alice Carrier,Pascal Salin,Sylviane Lortet,Olga Corti

doi:10.1038/s41419-021-03742-4

Abstract

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.

Highlights

Autophagy dysregulation, inflammation, and oxidative stress are involved in cancer, type 2 diabetes, and agerelated neurodegenerative diseases (NDs)
The 561 nm/458 nm signal ratio, which reflects mitochondria delivered to the acidic lysosomal compartment, was decreased in dDOR knockout (KO) neurons and increased in neurons overexpressing dDOR (Fig. 5G, H). These findings show that dDOR acts as a positive regulator of basal mitophagy in neurons, a process minimally affected by dPINK1 or dParkin deficiency[33]
DDOR does not genetically interact with dPINK1 We explored the potential interplay between dDOR and the mitophagy-associated gene dPINK1 using the canonical model of dorsal longitudinal indirect adult flight muscles (DLM) that has been used to highlight the genetic interactions between dPINK1 and dParkin44,45. dDOR-F or dDOR-L overexpression partially rescued the mitochondrial alterations triggered by dPINK1 inactivation, including the reduced mitochondrial matrix fluorescent staining (Fig. 6A), the loss of mitochondrial membrane integrity (Fig. 6B), and the presence of abnormally enlarged mitochondria (Fig. 6A, B)

Summary

Introduction

Inflammation, and oxidative stress are involved in cancer, type 2 diabetes, and agerelated neurodegenerative diseases (NDs). Deficient expression of tumor protein 53-induced nuclear protein 1 (TP53INP1) has been identified as a factor linking these mechanisms in cancer and in metabolic syndrome[1]. Its role in NDs remains unexplored, TP53INP1 has been identified as a susceptibility gene for Alzheimer’s disease[2] shared with type 2 diabetes[3,4]. In (diabetes-and-obesity-regulated), both encoding dual regulators of transcription and macroautophagy[5] (here referred to as autophagy). TP53INP1 and TP53INP2 are encoded by Trp53inp[1] and Trp53inp[2], respectively. Drosophila melanogaster harbors only one homologous gene, dDOR5

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Conclusion