Optimizing Mouse Models of Neurodegenerative Disorders

Are Therapeutics in Sight?

Cathleen M Lutz; Melissa A Osborne


Future Neurology. 2014;9(1):67-75. 

In This Article

Abstract and Introduction


The genomic and biologic conservation between mice and humans, along with our increasing ability to manipulate the mouse genome, places the mouse as a premier model for deciphering disease mechanisms and testing potential new therapies. Despite these advantages, mouse models of neurodegenerative disease are sometimes difficult to generate and can present challenges that must be carefully addressed when used for preclinical studies. For those models that do exist, the standardization and optimization of the models is a critical step in ensuring success in both basic research and preclinical use. This review looks back on the history of model development for neurodegenerative diseases and highlights the key strategies that have been learned in order to improve the design, development and use of mouse models in the study of neurodegenerative disease.


The mouse has long been recognized to be a powerful tool in elucidating the genetics and pathophysiology of human disease.[1] However, neurodegenerative mouse models are particularly scarce and can be challenging to use for preclinical studies. Many neurodegenerative diseases seen in humans simply do not occur naturally in mice, implying that that underlying disease mechanisms and biology may drastically differ between the two species. In addition, many neurodegenerative diseases seen in humans involve an aging component. Diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) can take decades to manifest in humans. The lifespan of a mouse may not be long enough for such deficits to be revealed. However, the ease by which we can manipulate the mouse genome has resulted in a number of transgenic and knockout mouse models over the last decade that have allowed us to push the onset of neurodegenerative disease manifestation in the mouse through overexpression and tissue-specific expression. Even with these systems, it remains unclear how well these models recapitulate the deficits seen in the CNS of patients, or how directly the data obtained from these models will translate into clinical trials. Failed clinical trials, especially in the field of ALS, have caused many researchers to question whether the mouse is a good model for translating therapeutic efficacy (reviewed in [2], and see [3,4]). The answer to this question may vary depending on the disease or the model used, but invariably, we can improve the way in which we approach the design of clinical trials, as well as the rigor with which preclinical studies are performed. Recent attention has focused on calling for greater transparency and rigor in preclinical efficacy testing studies, citing a number of reasons for reporting biases.[5] Adherence to better preclinical trial design will no doubt improve the reproducibility of published findings. In the spirit of improving preclinical studies, this review takes one step further in terms of the mouse models themselves. While no mouse model is likely to recapitulate all aspects of a disease, we can greatly improve their usefulness by applying higher standards and scrutiny to model design, standardization, use and the interpretation of research results. We will use our experience in ALS, Friedreich's ataxia (FRDA) and spinal muscular atrophy (SMA) in order to examine what we have learned that is changing the way we move forward in mouse model development.