Impaired mitochondrial dynamics underlie axonal defects in hereditary spastic paraplegias

Hum Mol Genet. 2018 Jul 15;27(14):2517-2530. doi: 10.1093/hmg/ddy156.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics*
  • Axons / drug effects
  • Axons / pathology
  • Carrier Proteins / genetics*
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • GTP Phosphohydrolases / genetics*
  • Humans
  • Induced Pluripotent Stem Cells
  • Membrane Potential, Mitochondrial / genetics
  • Mesencephalon / metabolism
  • Mesencephalon / pathology
  • Microtubule-Associated Proteins / genetics*
  • Mitochondria / genetics
  • Mitochondria / pathology
  • Mitochondrial Dynamics / genetics
  • Mitochondrial Proteins / genetics*
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Mutation
  • Neuronal Outgrowth / drug effects
  • Neuronal Outgrowth / genetics
  • Quinazolinones / pharmacology
  • Spastic Paraplegia, Hereditary / drug therapy
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / physiopathology

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • AP5Z1 protein, human
  • Adaptor Proteins, Vesicular Transport
  • Carrier Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Quinazolinones
  • spastizin protein, human
  • GTP Phosphohydrolases
  • DNM1L protein, human