Increase of Parkin and ATG5 plasmatic levels following perinatal hypoxic-ischemic encephalopathy

Anna Tarocco, Giampaolo Morciano, Mariasole Perrone, Claudia Cafolla, Cristina Ferrè, Tiziana Vacca, Ginevra Pistocchi, Fabio Meneghin, Ilaria Cocchi, Gianluca Lista, Irene Cetin, Pantaleo Greco, Giampaolo Garani, Marcello Stella, Miria Natile, Gina Ancora, Immacolata Savarese, Francesca Campi, Iliana Bersani, Andrea Dotta, Eloisa Tiberi, Giovanni Vento, Elisabetta Chiodin, Alex Staffler, Eugenia Maranella, Sandra Di Fabio, Mariusz R Wieckowski, Carlotta Giorgi, Paolo Pinton, Anna Tarocco, Giampaolo Morciano, Mariasole Perrone, Claudia Cafolla, Cristina Ferrè, Tiziana Vacca, Ginevra Pistocchi, Fabio Meneghin, Ilaria Cocchi, Gianluca Lista, Irene Cetin, Pantaleo Greco, Giampaolo Garani, Marcello Stella, Miria Natile, Gina Ancora, Immacolata Savarese, Francesca Campi, Iliana Bersani, Andrea Dotta, Eloisa Tiberi, Giovanni Vento, Elisabetta Chiodin, Alex Staffler, Eugenia Maranella, Sandra Di Fabio, Mariusz R Wieckowski, Carlotta Giorgi, Paolo Pinton

Abstract

Brain injury at birth is an important cause of neurological and behavioral disorders. Hypoxic-ischemic encephalopathy (HIE) is a critical cerebral event occurring acutely or chronically at birth with high mortality and morbidity in newborns. Therapeutic strategies for the prevention of brain damage are still unknown, and the only medical intervention for newborns with moderate-to-severe HIE is therapeutic hypothermia (TH). Although the neurological outcome depends on the severity of the initial insult, emerging evidence suggests that infants with mild HIE who are not treated with TH have an increased risk for neurodevelopmental impairment; in the current clinical setting, there are no specific or validated biomarkers that can be used to both correlate the severity of the hypoxic insult at birth and monitor the trend in the insult over time. The aim of this work was to examine the presence of autophagic and mitophagic proteins in bodily fluids, to increase knowledge of what, early at birth, can inform therapeutic strategies in the first hours of life. This is a prospective multicentric study carried out from April 2019 to April 2020 in eight third-level neonatal intensive care units. All participants have been subjected to the plasma levels quantification of both Parkin (a protein involved in mitophagy) and ATG5 (involved in autophagy). These findings show that Parkin and ATG5 levels are related to hypoxic-ischemic insult and are reliable also at birth. These observations suggest a great potential diagnostic value for Parkin evaluation in the first 6 h of life.

Trial registration: ClinicalTrials.gov NCT03897101.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Investigation of mitophagy in newborns at birth and correlation with clinical endpoints. (A) Parkin plasma levels measured by ELISA in healthy, babies not needing TH and severe HIE newborns. (B) Correlation between Parkin and pH at birth. (C) Parkin level stratification according to the base excess score in the whole cohort. (D) Correlation between Parkin and lactate release at birth. (E) Parkin level stratification according to resuscitation-at- birth score in the whole cohort (0–1 = CPAP assistance, 2–5 = from PPV to drugs). (F) Parkin level stratification according to Apgar score at 5 min in the whole cohort.
Figure 2
Figure 2
Investigation of autophagy in newborns at birth and correlation with clinical endpoints. (A) ATG5 plasma levels measured by ELISA in healthy, babies not needing TH and severe HIE newborns. (B) Correlation between ATG5 and pH at birth. (C) ATG5 level stratification according to base excess score in the whole cohort. (D) Correlation between ATG5 and lactate release at birth. (E) ATG5 level stratification according to resuscitation at birth score in the whole cohort (0–1 = CPAP assistance, 2–5 = from PPV to drugs). (F) ATG5 level stratification according to Apgar score at 5 min in the whole cohort.
Figure 3
Figure 3
Mitophagy and autophagy changes overtime. (A) Parkin plasma levels measured by ELISA in healthy, babies not needing TH and severe HIE newborns at T1 (72 h) and at T2 (7 days), as well as at birth. (B) ATG5 plasma levels measured by ELISA in healthy, MAB group and severe HIE newborns at T1 (72 h) and at T2 (7 days), as well as at birth.
Figure 4
Figure 4
Stratification of Parkin levels in the Group B. Parkin level stratification according to pH (A), base excess (B), lactates (C), CPR (D) and Apgar score at 5 min (E) in Group B.

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