Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson's Disease

Paola Imbriani, Annalisa Tassone, Maria Meringolo, Giulia Ponterio, Graziella Madeo, Antonio Pisani, Paola Bonsi, Giuseppina Martella

Research output: Contribution to journalArticle

Abstract

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson's disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Volume20
Issue number14
DOIs
Publication statusPublished - Jul 11 2019

Fingerprint

Parkinson disease
Caspase 3
mice
Parkinson Disease
Phosphotransferases
Cell death
amphetamines
Plasticity
Neuronal Plasticity
Chemical activation
apoptosis
Depression
plastic properties
Phosphatases
knockout mice
Amphetamine
Caspases
activation
Brain
axons

Keywords

  • caspase-3
  • long-term depression
  • Parkinson’s disease
  • PINK1
  • striatum
  • synaptic plasticity

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson's Disease. / Imbriani, Paola; Tassone, Annalisa; Meringolo, Maria; Ponterio, Giulia; Madeo, Graziella; Pisani, Antonio; Bonsi, Paola; Martella, Giuseppina.

In: International Journal of Molecular Sciences, Vol. 20, No. 14, 11.07.2019.

Research output: Contribution to journalArticle

Imbriani, Paola ; Tassone, Annalisa ; Meringolo, Maria ; Ponterio, Giulia ; Madeo, Graziella ; Pisani, Antonio ; Bonsi, Paola ; Martella, Giuseppina. / Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson's Disease. In: International Journal of Molecular Sciences. 2019 ; Vol. 20, No. 14.
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