Phenotype assessment for neurodegenerative murine models with ataxia and application to Niemann–Pick disease, type C1

Biology Open

Craig B. Abbott¹  Rachel Luke¹  Niamh X. Cawley¹  Forbes D. Porter¹  Julia Yerger¹  Antony C. Cougnoux¹  Tannia S. Clark²  Cristin D. Davidson² 

[1]Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Molecular Dysmorphology, NIH, Bethesda, MD, 20892, USA

[2]National Human Genome Research Institute, Genetic Disease Research Branch, NIH, Bethesda, MD 20892, USA

关键词: niemann–pick disease;    type c;    cerebellar ataxia;    npc1;    neurological disease;    phenotype assessment;    lysosomal disease;   

DOI  :  10.1242/bio.059052

来源: DOAJ

【 摘 要 】

Identifying meaningful predictors of therapeutic efficacy from preclinical studies is challenging. However, clinical manifestations occurring in both patients and mammalian models offer significant translational value. Many neurological disorders, including inherited, metabolic Niemann–Pick disease, type C (NPC), exhibit ataxia. Both individuals with NPC and murine models manifest ataxia, and investigational therapies impacting this phenotype in mice have been reported to slow disease progression in patients (e.g. miglustat, intrathecal 2-hydroxypropyl-beta-cyclodextrin, and acetyl-L-leucine). Reproducible phenotypic scoring of animal models can facilitate comparisons between genotypes, sexes, disease course, and therapies. Previously, other groups have developed a composite phenotypic scoring system (CPSS), which was subsequently used to distinguish strain-dependent phenotypes and, with modifications, to evaluate potential therapies. However, high inter-rater reliability is paramount to widespread use. We have created a comprehensive, easy-to-follow phenotypic assessment based on the CPSS and have verified its reproducibility using murine models of NPC disease. Application of this scoring system is not limited to NPC disease and may be applicable to other models of neurodegeneration exhibiting motor incoordination, thereby increasing its utility in translational studies.

【 授权许可】

Unknown