New cellular imaging-based method to distinguish SPG4 subtype of Hereditary Spastic Paraplegia

Background and purpose: Microtubule defects are a common feature in several neurodegenerative disorders, including the 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: We developed an automated, simple, fast, and non-invasive cell imaging-based method to quantify microtubule Cytoskeleton organization changes in lymphoblastoid cells and peripheral blood mononuclear cells.

Results: We 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, we show 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.