Through this project, we will develop human stem cell models for a rare disorder known as spinocerebellar ataxia type 7 (SCA7). Although SCA7 is rare, it shares important features with very common neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). All these diseases are caused by proteins that misfold to form toxic proteins that damage and kill neurons. We are yet to fully understand how this occurs, but we think that misfolded proteins derail normal processes that the disease protein usually regulates. SCA7 patients display an unique disease symptom – they go blind due to retinal degeneration. In this project, we will create stem cell models for SCA7 retinal degeneration to understand how the SCA7 disease protein causes retinal neurons to die. Our studies will establish the best method for creating retinal neurons from human stem cells made from a patient’s skin. This advance will be important for future experiments on all eye diseases that cause blindness due to retinal disease, including common disorders such as age-related macular generation. By figuring out how the SCA7 disease protein leads to degeneration of retinal neurons, we will gain insights into how disease proteins in AD, PD, and ALS cause neuron toxicity and death. Finally, the knowledge that we acquire from this project will allow us to develop new treatments for SCA7 and for these other more common neurological diseases.
Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), take a great toll on the health, productivity, and emotional well-being of affected patients and their families. With our population aging, we need to make progress in understanding how such diseases occur so that we can come up with new therapies. Decades of biomedical research has taught us that we can learn a great deal from studying rare diseases that are closely related to more common disorders. Indeed, in the late 1990's, studies of spinocerebellar ataxia type (SCA7) coalesced with studies on prion diseases (that causes mad-cow disease), PD, and AD to lead to the realization that all neurodegenerative diseases share a common feature of being caused by a misfolded protein that becomes toxic. We believe that a careful study of SCA7 through stem cell modeling will provide important information for how to approach more common disorders, such as AD and PD. We are also convinced that we can use SCA7 as a proof-of-principle to create reliable methods to model eye diseases that cause blindness in people, and expect that this information will fuel advances in understanding more common retinal disorders, such as age-related macular degeneration. It is also possible that therapies discovered for SCA7 will shed light on powerful strategies to treat related neurological disorders, such as AD and PD.