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

Abstract 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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Gautam Wali, Shlomo Berkovsky, Daniel R. Whiten, Alan Mackay-Sim, Carolyn M. Sue
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8ca07526bb474194b884a6feb2839f05
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:8ca07526bb474194b884a6feb2839f05
record_format	dspace
spelling	oai:doaj.org-article:8ca07526bb474194b884a6feb2839f052021-12-02T18:51:42ZSingle cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia10.1038/s41598-021-95995-42045-2322https://doaj.org/article/8ca07526bb474194b884a6feb2839f052021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95995-4https://doaj.org/toc/2045-2322Abstract 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.Gautam WaliShlomo BerkovskyDaniel R. WhitenAlan Mackay-SimCarolyn M. SueNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gautam Wali Shlomo Berkovsky Daniel R. Whiten Alan Mackay-Sim Carolyn M. Sue Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia
description	Abstract 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.
format	article
author	Gautam Wali Shlomo Berkovsky Daniel R. Whiten Alan Mackay-Sim Carolyn M. Sue
author_facet	Gautam Wali Shlomo Berkovsky Daniel R. Whiten Alan Mackay-Sim Carolyn M. Sue
author_sort	Gautam Wali
title	Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia
title_short	Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia
title_full	Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia
title_fullStr	Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia
title_full_unstemmed	Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia
title_sort	single cell morphology distinguishes genotype and drug effect in hereditary spastic paraplegia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8ca07526bb474194b884a6feb2839f05
work_keys_str_mv	AT gautamwali singlecellmorphologydistinguishesgenotypeanddrugeffectinhereditaryspasticparaplegia AT shlomoberkovsky singlecellmorphologydistinguishesgenotypeanddrugeffectinhereditaryspasticparaplegia AT danielrwhiten singlecellmorphologydistinguishesgenotypeanddrugeffectinhereditaryspasticparaplegia AT alanmackaysim singlecellmorphologydistinguishesgenotypeanddrugeffectinhereditaryspasticparaplegia AT carolynmsue singlecellmorphologydistinguishesgenotypeanddrugeffectinhereditaryspasticparaplegia
_version_	1718377395740737536

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

Ejemplares similares