Cell mechanism behind SPG7 discovered

Drug treatment to correct impairment identified

Prof Casari

The nature of the disease-causing process involving the mitochondrial network in SPG7 has been discovered using both cells from people with SPG7 and mice with SPG7 in experiments.


Drug treatment with the benzodiazepine Bz-423 normalises nerve impulses and restores mobility in the SPG7 mice, so establishing the potential for a therapy for SPG7.

Background: Mutations of the mitochondrial protein paraplegin cause hereditary spastic paraplegia type 7 (SPG7), a so-far untreatable degenerative disease of the upper motor neuron 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 patient-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.

SOURCE: EBioMedicine. 2020 Oct 9;61:103050. doi: 10.1016/j.ebiom.2020.103050. Online ahead of print. PMID: 33045469 Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia

Irene Sambri  1 Filomena Massa  1 Francesca Gullo  2 Simone Meneghini  2 Laura Cassina  3 Michela Carraro  4 Giorgia Dina  3 Angelo Quattrini  3 Lorenzo Patanella  1 Annamaria Carissimo  5 Antonella Iuliano  1 Filippo Santorelli  6 Franca Codazzi  7 Fabio Grohovaz  7 Paolo Bernardi  4 Andrea Becchetti  2 Giorgio Casari  8

  1. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli-Naples, Italy.
  2. University of Milano-Bicocca, Milan, Italy.
  3. San Raffaele Scientific Institute, Milan, Italy.
  4. University of Padua, Padua, Italy.
  5. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli-Naples, Italy; Institute for Applied Mathematics ‘Mauro Picone’, National Research Council, Naples, Italy.
  6. RCCS Fondazione Stella Maris, Pisa, Italy.
  7. Vita-Salute San Raffaele University, Milan, Italy.
  8. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli-Naples, Italy; Vita-Salute San Raffaele University, Milan, Italy


    1. Editor’s Note: The research reported is just the start of the process of trying to translate this important finding into a successful treatment. More studies on the mechanism will be carried out. More studies on the effect of the candidate drug on experimental animals with SPG7 will take place. There may be human stem cell studies in SPG7 to help assess the potential for the drug therapy.
      Only if and when the results of all that research is positive, could clinical trials be undertaken to determine the safety and effectiveness of the drug treatment in people with SPG7.
      So it is likely that this treatment, if proven successful, would not be available for at least a few years yet. Research developments will be reported on in the quarterly website updates as they are published.

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