Impaired mitochondria cause SPGs 11 & 48

Compound found that restores function

A compound known as P110 with the potential to be an effective treatment for SPGs 11 and 48 restores mitochondrial structure and function in impaired stem cells in the lab.

Degeneration in SPG11 and SPG48 neurons is shown to be caused by impaired mitochondrial dynamics leading to structural disorganisation and axonal degeneration in the cells.

Using different established methods for preventing mitochondrial impairment in these cells leads to mitigation or full restoration of multiple structures and functions measured.


Hereditary spastic paraplegias (HSPs) are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive HSPs, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1.

Using the integration-free episomal method, we established SPG11 patient-specific induced pluripotent stem cells (iPSCs) from patient fibroblasts. We differentiated SPG11 iPSCs, as well as SPG48 iPSCs previously established, into cortical projection neurons (PNs) and examined protective effects by targeting mitochondrial dynamics using P110, a peptide that selectively inhibits mitochondrial fission GTPase Drp1. P110 treatment mitigates mitochondrial fragmentation, improves mitochondrial motility, and restores mitochondrial health and ATP levels in SPG11 and SPG48 neurons.

Neurofilament (NF) aggregations are increased in SPG11 and SPG48 axons, and these are also suppressed by P110. Similarly, P110 mitigates NF disruption in both SPG11 and SPG48 knockdown cortical PNs, confirming the contribution of HSP gene deficiency to subsequent NF and mitochondrial defects. Strikingly, NF aggregations in SPG11 and SPG48 deficient neurons double stain with ubiquitin and autophagy related proteins, resembling the pathological hallmark observed in SPG11 autopsy brain sections.

To confirm the cause-effect relationship between the SPG11 mutations and disease phenotypes, we knocked-in SPG11 disease mutations to human embryonic stem cells (hESCs) and differentiated these stem cells into cortical PNs. Reduced ATP levels and accumulated NF aggregations along axons are observed, and both are mitigated by P110. Furthermore, rescue experiment with expression of wildtype SPG11 in cortical PNs derived from both SPG11 patient iPSCs and SPG11 disease mutation knock-in hESCs leads to rescue of mitochondrial dysfunction and NF aggregations in these SPG11 neurons. Finally, in SPG11 and SPG48 long-term cultures, increased release of phosphoNF-H, a biomarker for nerve degeneration, is significantly reduced by inhibiting mitochondrial fission pharmacologically using P110 and genetically using Drp1 shRNA.

Taken together, our results demonstrate that impaired mitochondrial dynamics underlie both cytoskeletal disorganization and axonal degeneration in SPG11 and SPG48 neurons, highlighting the importance of targeting these pathologies therapeutically.

SOURCE:  Brain. 2022 Jan 13;awab488.  doi: 10.1093/brain/awab488. Online ahead of print. PMID: 35026838 © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons

Zhenyu Chen  1   2 Eric Chai  1 Yongchao Mou  1   2 Ricardo H Roda  3   4 Craig Blackstone  3   5   6 Xue-Jun Li  1   2

1. Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL 61107, USA.

2. Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, USA.

3. Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

4. Department of Neurology, Johns Hopkins University of Medicine, Baltimore, MD 21205, USA.

5. Movement Disorders Division, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.

6. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA.

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