The Mitochondrial Permeability Transition Pore as a Key Player in SPG7 Hereditary Spastic Paraplegia: A Mechanistic Study Toward a Therapeutic Approach
Abstract
Mutations of paraplegin are the causative event of a recessive form of hereditary spastic paraplegia type 7 (SPG7). Paraplegin localizes in endocellular organelles, the mitochondria, where it exerts the activity of quality control on the mitochondrial proteins. A recent report attributes a new function to paraplegin, as a novel regulator of the so-called mitochondrial permeability transition, PTP for short. This is an intra-organellar structure that, in peculiar metabolic condition of the mitochondria, leads to the release of the proteins and solutes from the organelle into the surrounding cytoplasm. This can then trigger the pathway of programmed cell death. The activity of mitochondria is fundamental for the functioning of neurons, the cells affected in spastic paraplegia neurodegeneration, and particularly at the synapses where the regulation of PTP is crucial for neuronal synaptic activity. We propose that PTP is an essential and previously unrecognized actor of SPG7 neurodegeneration and, capitalizing on our cell and animal models of SPG7, we intend to test this new hypothesis of pathogenesis. Taking advantage of the recent and quickly developing field of PTP pharmacology, we also propose to rescue the neurodegeneration of the SPG7 preclinical model by small molecule PTP modulators.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810001
Entities
People
- Giorgio Casari
Organizations
- San Raffaele Hospital
- United States Army