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The most frequent form of hereditary spastic paraplegia is caused by mutations in the <jats:italic>SPG4<\/jats:italic>\/<jats:italic>SPAST<\/jats:italic> gene, encoding the microtubule severing enzyme spastin. To date, there is no effective therapy available but spastin\u2010enhancing therapeutic approaches are emerging; thus prognostic and predictive biomarkers are urgently required.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An automated, simple, fast and non\u2010invasive cell imaging\u2010based method was developed to quantify microtubule cytoskeleton organization changes in lymphoblastoid cells and peripheral blood mononuclear cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>It was observed that lymphoblastoid cells and peripheral blood mononuclear cells from individuals affected by <jats:italic>SPG4<\/jats:italic>\u2010hereditary spastic paraplegia show a polarized microtubule cytoskeleton organization. In a pilot study on freshly isolated peripheral blood mononuclear cells, our method discriminates <jats:italic>SPG4<\/jats:italic>\u2010hereditary 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings open the possibility of a rapid, non\u2010invasive, inexpensive test useful to recognize <jats:italic>SPG4<\/jats:italic>\u2010hereditary spastic paraplegia subtype and evaluate the effects of spastin\u2010enhancing drug in non\u2010neuronal cells.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.15756","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T10:20:30Z","timestamp":1677147630000},"page":"1734-1744","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["New cellular imaging\u2010based method to distinguish the <scp>SPG4<\/scp> subtype of hereditary spastic 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