MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons

Clin Sci (Lond). 2019 Feb 22;133(4):583-595. doi: 10.1042/CS20180980. Print 2019 Feb 28.


Recent reports, including ours, have indicated that microRNA (miR)-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a potential therapeutic target for the treatment of atherosclerosis. Here, we show that SPAST, which encodes a microtubule-severing protein called SPASTIN, was a novel target gene of miR-33 in human. Actually, the miR-33 binding site in the SPAST 3'-UTR is conserved not in mice but in mid to large mammals, and it is impossible to clarify the role of miR-33 on SPAST in mice. We demonstrated that inhibition of miR-33a, a major form of miR-33 in human neurons, via locked nucleic acid (LNA)-anti-miR ameliorated the pathological phenotype in hereditary spastic paraplegia (HSP)-SPG4 patient induced pluripotent stem cell (iPSC)-derived cortical neurons. Thus, miR-33a can be a potential therapeutic target for the treatment of HSP-SPG4.

Keywords: human model; microRNA; paraplegia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Binding Sites
  • Cells, Cultured
  • Gene Expression Regulation
  • Genetic Therapy / methods*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Neurites / metabolism*
  • Neurites / pathology
  • Neurogenesis
  • Oligonucleotides / genetics*
  • Oligonucleotides / metabolism
  • Phenotype
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / metabolism
  • Spastic Paraplegia, Hereditary / pathology
  • Spastic Paraplegia, Hereditary / therapy*
  • Spastin / genetics*
  • Spastin / metabolism


  • 3' Untranslated Regions
  • MIRN33a microRNA, human
  • MicroRNAs
  • Oligonucleotides
  • locked nucleic acid
  • Spastin
  • SPAST protein, human