Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia

Sci Rep. 2021 Aug 17;11(1):16635. doi: 10.1038/s41598-021-95995-4.


A central need for neurodegenerative diseases is to find curative drugs for the many clinical subtypes, the causative gene for most cases being unknown. This requires the classification of disease cases at the genetic and cellular level, an understanding of disease aetiology in the subtypes and the development of phenotypic assays for high throughput screening of large compound libraries. Herein we describe a method that facilitates these requirements based on cell morphology that is being increasingly used as a readout defining cell state. In patient-derived fibroblasts we quantified 124 morphological features in 100,000 cells from 15 people with two genotypes (SPAST and SPG7) of Hereditary Spastic Paraplegia (HSP) and matched controls. Using machine learning analysis, we distinguished between each genotype and separated them from controls. Cell morphologies changed with treatment with noscapine, a tubulin-binding drug, in a genotype-dependent manner, revealing a novel effect on one of the genotypes (SPG7). These findings demonstrate a method for morphological profiling in fibroblasts, an accessible non-neural cell, to classify and distinguish between clinical subtypes of neurodegenerative diseases, for drug discovery, and potentially for biomarkers of disease severity and progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics
  • Disease Progression
  • Genotype*
  • Humans
  • Machine Learning
  • Metalloendopeptidases / genetics
  • Mutation
  • Pharmaceutical Preparations*
  • Severity of Illness Index
  • Single-Cell Analysis / methods*
  • Spastic Paraplegia, Hereditary / drug therapy
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / pathology*
  • Spastin / genetics


  • Pharmaceutical Preparations
  • Metalloendopeptidases
  • SPG7 protein, human
  • ATPases Associated with Diverse Cellular Activities
  • Spastin
  • SPAST protein, human