Mitochondrial function study in HSP

New findings about SPG7 and SPG4

This study is the first to measure multiple impairments in mitochondrial structure, function and proliferation where there have been increased levels of paraplegin that occurs in some SPG7 mutations. The mitochondrial dysfunction was found to be similar to that found in previous studies where paraplegin is deficient in other SPG7 mutations.

The study also importantly showed that SPG4 HSP does not have such dysfunction, displaying mitochondrial functions similar to healthy control cells.

Long-term member of the HSP Research Program team, Gautam Wali, headed this important study of mitochondrial function in SPG7 and SPG4 types of HSP.

Gautam Wali


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 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 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.

See the entire article here:

SOURCE: Front. Neurosci., 20 August 2020

Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits in SPG7 but Not SPAST Patient-Derived Stem Cells

Gautam Wali1,2*†, Kishore Kumar1,2,3,4,5, Erandhi Liyanage 1, Ryan Davis 1,2,4, Alan Mackay-Sim 2,6† and Carolyn Sue1,2,5*†

  1. Department of Neurogenetics, Royal North Shore Hospital, Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia
  2. Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
  3. Molecular Medicine Laboratory, Department of Neurology, Concord Hospital, Sydney, NSW, Australia
  4. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia
  5. Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia
  6. Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia

1 comment

  1. I suffer from spg4 and if you need to try any medication I’m willing to participate to see if I can help out in any way

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