The Ubiquitin System in Neurodegeneration

Distinguished Professor Aaron Ciechanover
2004 Nobel Prize Laureate in Chemistry

Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and polyglutamine (PolyQ) expansion disorders such as Huntington’s disease (HD) are all neurodegenerative disorders characterized by distinct abnormal cognitive/behavioral and movement symptoms.

Despite being distinct clinical entities, these diseases have in common several underlying mechanisms. They are all characterized by selective and progressive cell death, the prevention of which has been the main focus of research for many years. Current views of these disorders consider them as a cohesive group of “pathologies of proteotoxicity” of the nervous system. They were assembled together into this group as they share a common hallmark of aggregation of specific disease-related proteins that gradually accumulate into harmful inclusions in defined cells of the brain. The inclusions are thought to have a protective role at the initial stages of the disease, where soluble aggregated proteins are accumulated, and their toxic effect is prevented.  Later however, as they grow in volume, they become toxic, which results in impairment of many vital cellular functions leading to gradual cell loss. Specifically, there are neurofibrillary tangles in AD, Lewy bodies in PD, Bunina bodies in ALS, and PolyQ inclusion bodies in HD and Spinocerebellar Ataxias. Clearly, the aggregates constitute a fundamental feature in the pathology and progression of these diseases. Therefore, understanding this key process in one disorder might have broader implications on other diseases in the group.

In light of the similarities between the diseases, we have decided to focus our research on HD. The genetic cause of HD, unlike AD, is well defined and has been studied extensively. Importantly, relatively simple molecular tools are available to that enable manipulation of cell models, neurons, and model organisms that faithfully reproduce the disease. Therefore, we took advantage of a novel HD rat model to address questions regarding the mechanism of aggregates formation in the pathology of HD.

We have already identified several candidate genes that might shed light on cellular events that are affected by the pathology. We shall further explore these candidates by using our laboratory established research tools.Aaron Ciechanover