TY - JOUR
T1 - Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia
AU - Sambri, Irene
AU - Massa, Filomena
AU - Gullo, Francesca
AU - Meneghini, Simone
AU - Cassina, Laura
AU - Carraro, Michela
AU - Dina, Giorgia
AU - Quattrini, Angelo
AU - Patanella, Lorenzo
AU - Carissimo, Annamaria
AU - Iuliano, Antonella
AU - Santorelli, Filippo
AU - Codazzi, Franca
AU - Grohovaz, Fabio
AU - Bernardi, Paolo
AU - Becchetti, Andrea
AU - Casari, Giorgio
N1 - Funding Information:
We thank Leopoldo Staiano for critical discussion, Maurizio De Fusco for obtaining the SPG7?/? HEK293 clones, and Barbara Tumaini for FACS-sorter assistance. This work was supported by, and we are grateful to, Telethon Foundation (TIGEM grant) and Dept. of Defense, US Army (grant W81XWH-18-1-0001), University of Milano-Bicocca (FAR 2018). SM is a recipient of a post-doctoral fellowship awarded by the University of Milano-Bicocca. All reagents used in this work are available upon request and a brief statement describing the purpose for their use.
Funding Information:
We thank Leopoldo Staiano for critical discussion, Maurizio De Fusco for obtaining the SPG7 −/− HEK293 clones, and Barbara Tumaini for FACS-sorter assistance. This work was supported by, and we are grateful to, Telethon Foundation (TIGEM grant) and Dept. of Defense, US Army (grant W81XWH-18-1-0001 ), University of Milano-Bicocca ( FAR 2018 ). SM is a recipient of a post-doctoral fellowship awarded by the University of Milano-Bicocca .
Publisher Copyright:
© 2020 The Authors
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - Background: Mutations of the mitochondrial protein paraplegin cause hereditary spastic paraplegia type 7 (SPG7), a so-far untreatable degenerative disease of the upper motoneuron with still undefined pathomechanism. The intermittent mitochondrial permeability transition pore (mPTP) opening, called flickering, is an essential process that operates to maintain mitochondrial homeostasis by reducing intra-matrix Ca2+ and reactive oxygen species (ROS) concentration, and is critical for efficient synaptic function. Methods: We use a fluorescence-based approach to measure mPTP flickering in living cells and biochemical and molecular biology techniques to dissect the pathogenic mechanism of SPG7. In the SPG7 animal model we evaluate the potential improvement of the motor defect, neuroinflammation and neurodegeneration by means of an mPTP inducer, the benzodiazepine Bz-423. Findings: We demonstrate that paraplegin is required for efficient transient opening of the mPTP, that is impaired in both SPG7 patients-derived fibroblasts and primary neurons from Spg7−/− mice. We show that dysregulation of mPTP opening at the pre-synaptic terminal impairs neurotransmitter release leading to ineffective synaptic transmission. Lack of paraplegin impairs mPTP flickering by a mechanism involving increased expression and activity of sirtuin3, which promotes deacetylation of cyclophilin D, thus hampering mPTP opening. Pharmacological treatment with Bz-423, which bypasses the activity of CypD, normalizes synaptic transmission and rescues the motor impairment of the SPG7 mouse model. Interpretation: mPTP targeting opens a new avenue for the potential therapy of this form of spastic paraplegia. Funding: Telethon Foundation grant (TGMGCSBX16TT); Dept. of Defense, US Army, grant W81XWH-18–1–0001
AB - Background: Mutations of the mitochondrial protein paraplegin cause hereditary spastic paraplegia type 7 (SPG7), a so-far untreatable degenerative disease of the upper motoneuron with still undefined pathomechanism. The intermittent mitochondrial permeability transition pore (mPTP) opening, called flickering, is an essential process that operates to maintain mitochondrial homeostasis by reducing intra-matrix Ca2+ and reactive oxygen species (ROS) concentration, and is critical for efficient synaptic function. Methods: We use a fluorescence-based approach to measure mPTP flickering in living cells and biochemical and molecular biology techniques to dissect the pathogenic mechanism of SPG7. In the SPG7 animal model we evaluate the potential improvement of the motor defect, neuroinflammation and neurodegeneration by means of an mPTP inducer, the benzodiazepine Bz-423. Findings: We demonstrate that paraplegin is required for efficient transient opening of the mPTP, that is impaired in both SPG7 patients-derived fibroblasts and primary neurons from Spg7−/− mice. We show that dysregulation of mPTP opening at the pre-synaptic terminal impairs neurotransmitter release leading to ineffective synaptic transmission. Lack of paraplegin impairs mPTP flickering by a mechanism involving increased expression and activity of sirtuin3, which promotes deacetylation of cyclophilin D, thus hampering mPTP opening. Pharmacological treatment with Bz-423, which bypasses the activity of CypD, normalizes synaptic transmission and rescues the motor impairment of the SPG7 mouse model. Interpretation: mPTP targeting opens a new avenue for the potential therapy of this form of spastic paraplegia. Funding: Telethon Foundation grant (TGMGCSBX16TT); Dept. of Defense, US Army, grant W81XWH-18–1–0001
KW - Hereditary spastic paraplegia
KW - Mitochondria
KW - Paraplegin
KW - Permeability transition pore
KW - SPG7
KW - Synaptic vesicles
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U2 - 10.1016/j.ebiom.2020.103050
DO - 10.1016/j.ebiom.2020.103050
M3 - Article
C2 - 33045469
AN - SCOPUS:85092141541
VL - 61
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
M1 - 103050
ER -