Sluggish mitochondrial flickering at the basis of Hereditary Spastic Paraplegia (SPG7)

Corticospinal tract degeneration is the cardinal feature of hereditary spastic paraplegia (HSP), a large group of rare genetic neurological diseases characterized by lower limb spasticity and weakness. Mutation in the SPG7 gene, which encodes the mitochondrial protein paraplegin, cause HSP type 7 (SPG7). Mitochondria play a key role in determining the cell fate during stress condition, through the mitochondrial permeability transition pore (mPTP), a non-selective channel that opens at high or low conductance mode. High conductance opening leads to cell death programs, conversely, intermittent fast opening and closing of the pore is essential for mitochondrial homeostasis, as it allows to effectively reduce intra-matrix concentration of Ca2+ and reactive oxygen species (ROS).  Moreover, mitochondria homeostasis at the synapse is tightly regulated by mPTP gating as neurons experience high metabolic demand during processes such as synaptic vesicle recycling, membrane potential maintenance, and Ca2+ exchange/extrusion. We assessed calcium retention capacity (CRC) on Spg7 KO HEK293 cells and found a consistent increase of CRC, thus indicating that the absence of paraplegin does modulate the regulation of mPTP opening.  The results demonstrate a pivotal role of paraplegin in mPTP modulation that have important consequences in terms of mechanism of disease and for designing an original therapeutic intervention for SPG7-HSP.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.