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Analyzing Mitochondrial Transport and Morphology in Human Induced Pluripotent Stem Cell-Derived Neurons in Hereditary Spastic Paraplegia
Published on: February 9, 2020
Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia
Irene Sambri1, Filomena Massa1, Francesca Gullo2
1Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli-Naples, Italy.
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.
Insights
Mitochondrial protein paraplegin mutations cause SPG7, a neurodegenerative disease. Targeting the mitochondrial permeability transition pore (mPTP) with Bz-423 rescues motor function in SPG7 mice, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Genetics
Background:
- Hereditary spastic paraplegia type 7 (SPG7) is a neurodegenerative disease caused by mutations in the mitochondrial protein paraplegin.
- The exact pathomechanism of SPG7 remains undefined.
- Mitochondrial permeability transition pore (mPTP) flickering is crucial for maintaining mitochondrial homeostasis and synaptic function.
Purpose of the Study:
- To investigate the role of paraplegin in mPTP flickering.
- To elucidate the pathomechanism of SPG7.
- To evaluate the therapeutic potential of mPTP inducers for SPG7.
Main Methods:
- Utilized fluorescence-based assays to measure mPTP flickering in living cells.
- Employed biochemical and molecular biology techniques to analyze SPG7 pathogenesis.
- Assessed motor function, neuroinflammation, and neurodegeneration in an SPG7 animal model using the mPTP inducer Bz-423.
Main Results:
- Paraplegin is essential for efficient mPTP flickering, which is impaired in SPG7 patient cells and Spg7 knockout mice.
- Dysfunctional mPTP opening in SPG7 leads to impaired neurotransmitter release and synaptic transmission deficits.
- Lack of paraplegin disrupts mPTP flickering via increased sirtuin3 activity, inhibiting cyclophilin D function.
- Bz-423 treatment normalized synaptic transmission and rescued motor impairments in SPG7 mice.
Conclusions:
- Targeting the mPTP presents a promising therapeutic strategy for SPG7.
- Restoring mPTP function can ameliorate motor deficits in SPG7.
- Understanding the role of paraplegin in mPTP regulation is key to developing treatments for SPG7.
