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

1
Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
2
Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
*
Author to whom correspondence should be addressed.
They are Co-first Authors.
They are Co-senior Authors.
Int. J. Mol. Sci. 2019, 20(14), 3407; https://doi.org/10.3390/ijms20143407
Received: 24 June 2019 / Revised: 4 July 2019 / Accepted: 9 July 2019 / Published: 11 July 2019
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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. View Full-Text
Keywords: Parkinson’s disease; PINK1; caspase-3; striatum; synaptic plasticity; long-term depression Parkinson’s disease; PINK1; caspase-3; striatum; synaptic plasticity; long-term depression
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Imbriani, P.; Tassone, A.; Meringolo, M.; Ponterio, G.; Madeo, G.; Pisani, A.; Bonsi, P.; Martella, G. Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson’s Disease. Int. J. Mol. Sci. 2019, 20, 3407.

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