Insights From Rare Disorders Shed Light on Common Neurodegenerative Diseases
Huda Y. Zoghbi, MD
Howard Hughes Medical Institute; Baylor College of Medicine and Director, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Texas, USA
Protein misfolding and accumulation are a common feature of a number of neurodegenerative diseases, from the idiopathic and all-too-common Alzheimer disease to the rare, inherited spinocerebellar ataxias. Studying spinocerebellar ataxia type 1 (SCA1), we discovered it is caused by expansion of a translated CAG repeat that encodes glutamines in Ataxin-1; this discovery made it possible to generate a mouse model in which a full-length protein bearing an expanded polyglutamine tract was targeted into the endogenous Ataxin-1 locus, closely reproducing the human disease. These Sca1154Q/+ mice taught us that the polyglutamine expansion makes mutant Ataxin-1 resist degradation, which slowly increases its steady-state levels, driving pathogenesis. More recently we began to dissect the factors that contribute to the vulnerability of specific neurons in SCA1 and we disocvered that Capicua, one of Ataxin-1's native partners, drives Purkinje cell toxicity. We also disovered that modest reductions of Ataxin-1 mitigate disease, which inspired us to perform cross-species genetic screens in human cells and fruit flies to identify modulators of Ataxin-1 levels. To date, we have identified dozens of regulators that are providing insight into Ataxin-1 biology and an avenue for the development of therapeutics. Given that elevated levels of amyloid precurosr protein APP, tau, and alpha-synuclein have been implicated in dementia and Parskinson disease, respectively, we have also performed cross-species genetic screens to identify modulators of these disease-driving proteins and so far have identified over 100 candidates. We predict that a combination therapy that partially inhibits two to three of the identified targets would reduce untoward side effects that might emerge from strong inhibition of any one target.
Funding: HHMI, NINDS, Bright Focus, JPB Foundation, Robert A. and Renee E. Belfer Family Foundation, UCB Pharmaceuticals, and the Chapman Foundation.