New cellular imaging-based method to distinguish the SPG4 subtype of hereditary spastic paraplegia

Eur J Neurol. 2023 Jun;30(6):1734-1744. doi: 10.1111/ene.15756. Epub 2023 Mar 26.


Background and purpose: Microtubule defects are a common feature in several neurodegenerative disorders, including hereditary spastic paraplegia. The most frequent form of hereditary spastic paraplegia is caused by mutations in the SPG4/SPAST gene, encoding the microtubule severing enzyme spastin. To date, there is no effective therapy available but spastin-enhancing therapeutic approaches are emerging; thus prognostic and predictive biomarkers are urgently required.

Methods: An automated, simple, fast and non-invasive cell imaging-based method was developed to quantify microtubule cytoskeleton organization changes in lymphoblastoid cells and peripheral blood mononuclear cells.

Results: It was observed that lymphoblastoid cells and peripheral blood mononuclear cells from individuals affected by SPG4-hereditary spastic paraplegia show a polarized microtubule cytoskeleton organization. In a pilot study on freshly isolated peripheral blood mononuclear cells, our method discriminates SPG4-hereditary spastic paraplegia from healthy donors and other hereditary spastic paraplegia subtypes. In addition, it is shown that our method can detect the effects of spastin protein level changes.

Conclusions: These findings open the possibility of a rapid, non-invasive, inexpensive test useful to recognize SPG4-hereditary spastic paraplegia subtype and evaluate the effects of spastin-enhancing drug in non-neuronal cells.

Keywords: SPG4; biomarker; hereditary spastic paraplegia; microtubule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Leukocytes, Mononuclear
  • Mutation
  • Pilot Projects
  • Spastic Paraplegia, Hereditary* / diagnostic imaging
  • Spastic Paraplegia, Hereditary* / genetics
  • Spastin / genetics


  • Spastin
  • SPAST protein, human