Rescue of mitochondrial and neurite pathology in SPG7 hereditary spastic paraplegia patient-derived cortical neurons.

Biallelic pathogenic variants in SPG7 are a frequent cause of hereditary spastic paraplegia leading to progressive disability due to a length-dependent degeneration of cerebellar and cortical projection neurons. While underlying mechanisms have been linked to impaired mitochondrial function, no disease-modifying therapy is available. We generated induced pluripotent stem cell-derived cortical neurons from SPG7 patients with non-sense or truncating variants and from matched controls. We performed detailed phenotyping of neuronal differentiation, as well as mitochondrial and neuritic morphology and function. We explored the effects of Bz-423, a modulator of the mitochondrial permeability transition pore, as a potential rescue of SPG7-specific cellular phenotypes. We successfully differentiated SPG7 patient-derived neurons, without quantitative differences in differentiation compared with controls. However, we delineate neurite-specific aberrations of mitochondrial morphology and ultrastructure. Moreover, anterograde axonal mitochondrial transport was impaired in SPG7. Exposure to Bz-423 rescued ultrastructural and functional phenotypes. In summary, our data show impaired neuritic mitochondria in a patient-specific human model, and we here demonstrate for the first time beneficial effects of Bz-423 on neuritic ultrastructure and function in a human neuronal SPG7 system. Moreover, we identify the mitochondrial permeability transition pore as a molecular target to rescue phenotypes also in carriers of non-sense or truncating SPG7 variants.