Introduction: Neurodegenerative diseases will increasingly be treated through neurosurgical interventions of neuromodulation, cell and viral implantations and other approaches to neuroregeneration. The development of such novel translational therapies depends heavily upon animal models. Promising medical therapies developed using mouse models have to date mostly failed in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level.
Methods: We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease using gene set enrichment analysis and complementary bioinformatic tools.
Results: Only 3 of 19 animal models evaluated showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated genes in human neurodegenerative diseases. Spearman’s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends towards preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance.
Conclusions: These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path forward to critically evaluate and improve animal models of human disease.
Patient Care: Awareness of the limitations of animal models can facilitate efforts to improve the translational research process.
Learning Objectives: Mouse models of neurodegeneration poorly represent human disease and provide a sub-optimal platform for development of novel neuroregenerative therapies