Mitochondrial impairment studied in SPG15 & 48 HSP

Function restored with treatment in lab experiments


Researcher Dr. June Li

Using stem cell derived neurons from skin samples of people with SPG15 and SPG48 HSP types, this study identified reductions in number, length and branching of axons and other outgrowths from different types of neurons.


Then, looking inside the cells, highly important organelles, mitochondria, showed significantly reduced lengths and densities in the axons or long arms of these neurons. As well as these structural defects, other tests confirmed impaired function as well, with a specific protein imbalance identified as the culprit.


Treating the HSP neurons in the laboratory with an organic compound, mdivi-1, restored balance in the mitochondria, reversed the impaired functions of the mitochondria and prevented death of the neurons, thus making it a potential treatment for types of HSP caused by the same or similar mechanisms.



Mechanisms by which long corticospinal axons degenerate in hereditary spastic paraplegia (HSP) are largely unknown. Here, we have generated induced pluripotent stem cells (iPSCs) from patients with two autosomal recessive forms of HSP, SPG15 and SPG48, which are caused by mutations in the ZFYVE26 and AP5Z1 genes encoding proteins in the same complex, the spastizin and AP5Z1 proteins, respectively.

. . .

In patient iPSC-derived telencephalic glutamatergic and midbrain dopaminergic neurons, neurite number, length and branching are significantly reduced, recapitulating disease-specific phenotypes. We analyzed mitochondrial morphology and noted a significant reduction in both mitochondrial length and their densities within axons of these HSP neurons. Mitochondrial membrane potential was also decreased, confirming functional mitochondrial defects. Notably, mdivi-1, an inhibitor of the mitochondrial fission GTPase DRP1, rescues mitochondrial morphology defects and suppresses the impairment in neurite outgrowth and late-onset apoptosis in HSP neurons. Furthermore, knockdown of these HSP genes causes similar axonal defects, also mitigated by treatment with mdivi-1. Finally, neurite outgrowth defects in SPG15 and SPG48 cortical neurons can be rescued by knocking down DRP1 directly.


Thus, abnormal mitochondrial morphology caused by an imbalance of mitochondrial fission and fusion underlies specific axonal defects and serves as a potential therapeutic target for SPG15 and SPG48.


SOURCE: Hum Mol Genet. 2018 May 2. doi: 10.1093/hmg/ddy156. [Epub ahead of print] PMID: 29726929


Impaired Mitochondrial Dynamics Underlie Axonal Defects in Hereditary Spastic Paraplegias.


Denton K1, Mou Y2,3, Xu CC2,3, Shah D2, Chang J4,5, Blackstone C4, Li XJ2,3.


1 Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA.

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

3 Department of Bioengineering, University of Illinois-Chicago, Chicago, IL 60607, USA.

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

5 Departments of Biomedical Science, Brain Science, and Neuroscience Graduate Program, Ajou University School of Medicine, Suwon 443-380, Korea.



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