Abstract
Mutations in SPG7 and SPAST are common causes of hereditary spastic paraplegia (HSP). While some SPG7 mutations cause paraplegin deficiency, other SPG7 mutations cause increased paraplegin expression. Mitochondrial function has been studied in models that are paraplegin-deficient (human, mouse, and Drosophila models with large exonic deletions, null mutations, or knockout models) but not in models of mutations that express paraplegin. Here, we evaluated mitochondrial function in olfactory neurosphere-derived cells, derived from patients with a variety of SPG7 mutations that express paraplegin and compared them to cells derived from healthy controls and HSP patients with SPAST mutations, as a disease control. We quantified paraplegin expression and an extensive range of mitochondrial morphology measures (fragmentation, interconnectivity, and mass), mitochondrial function measures (membrane potential, oxidative phosphorylation, and oxidative stress), and cell proliferation. Compared to control cells, SPG7 patient cells had increased paraplegin expression, fragmented mitochondria with low interconnectivity, reduced mitochondrial mass, decreased mitochondrial membrane potential, reduced oxidative phosphorylation, reduced ATP content, increased mitochondrial oxidative stress, and reduced cellular proliferation. Mitochondrial dysfunction was specific to SPG7 patient cells and not present in SPAST patient cells, which displayed mitochondrial functions similar to control cells. The mitochondrial dysfunction observed here in SPG7 patient cells that express paraplegin was similar to the dysfunction reported in cell models without paraplegin expression. The p.A510V mutation was common to all patients and was the likely species associated with increased expression, albeit seemingly non-functional. The lack of a mitochondrial phenotype in SPAST patient cells indicates genotype-specific mechanisms of disease in these HSP patients.
Highlights
Hereditary spastic paraplegia (HSP) is an inherited, progressive neurodegenerative condition causing spasticity and weakness in the lower limbs as a consequence of corticospinal tract degeneration (Hedera et al, 2005; Salinas et al, 2008; Kumar et al, 2015)
We show here that SPG7 patient ONS cells with compound heterozygous mutations have increased paraplegin expression accompanied by multiple mitochondrial dysfunctions, including aberrant mitochondrial morphology, reduced mitochondrial mass, reduced mitochondrial membrane potential, impaired oxidative phosphorylation, reduced ATP production and content, and increased oxidative stress
SPG7 patient cells showed reduced cellular proliferation. These cell function deficits were observed in all three SPG7 cell lines carrying different compound heterozygous mutations including a novel SPG7 mutation (NM_003119.3:c.1449 + 1G > A)
Summary
Hereditary spastic paraplegia (HSP) is an inherited, progressive neurodegenerative condition causing spasticity and weakness in the lower limbs as a consequence of corticospinal tract degeneration (Hedera et al, 2005; Salinas et al, 2008; Kumar et al, 2015). SPG7 mutations can cause loss of paraplegin (Atorino et al, 2003) or increased paraplegin expression (Thal et al, 2015; Pfeffer et al, 2014). The effects of SPG7 mutations leading to a loss of paraplegin expression on mitochondrial function have been characterized. Fibroblasts derived from a patient carrying a homozygous 9.5-kb deletion within the SPG7 gene that caused paraplegin deficiency exhibited impaired respiratory chain complex I activity. Consistent with this, a SPG7null mutant Drosophila model displayed reduced activity of respiratory chain complexes I and II, severely swollen and aberrantly shaped mitochondria in the synaptic terminals of photoreceptors, and neuronal and muscular degeneration (Pareek et al, 2018)
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