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Jeffery W. Kelly | |
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Protein misfolding diseases are becoming increasingly common as the population ages and as we improve the diagnosis of these pathologies. There are both loss-of-function and gain-of-toxic-function misfolding diseases. Examples of the former include Cystic Fibrosis, Gaucher disease and related lysosomal storage diseases. Loss-of-function diseases are typically caused by mutations that compromise folding in the secretory pathway, usually in the lumen of the endoplasmic reticulum (ER). Sustained chaperone binding in the ER lumen due to misfolding leads to dislocation to the cytoplasm and degradation of the protein by the proteasome, explaining the loss-of-function phenotype. Ironically, many of these variant proteins can fold and are functional in their destination environment, if they could just get there. We have developed small molecule chemical chaperones that stabilize the native state in the ER enabling the folding and trafficking of these variant proteins.
A major category of gain-of-toxic-function protein misfolding diseases are the amyloidoses. Systemic or tissue-localized deposition of fibrillar cross β-sheet aggregates of varying morphology appears to cause these diseases based on genetic and biochemical evidence. The formation of such aggregates causes devastating neurodegenerative diseases including Alzheimer’s disease (an extracellular misfolding disease) and Parkinson’s disease (an intracellular misfolding disease), which affect 50% and 5% of the individuals over 85 years old, respectively. As many as 30 different human proteins are amyloidogenic, leading to more than one hundred diseases owing to the unique pathology exhibited by mutations of a given amyloidogenic protein. The fibrils associated with each disease are largely composed of a single protein (e.g. the amyloid β-peptide deposits in the brain of Alzheimer’s disease subjects, α-synuclein deposits within the cytoplasm in the case of Parkinson’s disease, and transthyretin deposits in the peripheral nerves or heart of the familial amyloidoses patients).
Our laboratory is studying the mechanism of protein misfolding in numerous pathologies, striving to understand enough about the pathology so as to be able to design and synthesize small molecules that ameliorate these diseases. The molecules we have discovered to date, two of which are now being evaluated in human clinical trials, impose kinetic stabilization on the native state precluding misfolding and amyloid formation. In a new project, we also seek small molecules that influence intracellular protein translation, the unfolded protein response (by perturbing chaperone distribution, concentration, and folding enzyme activities) and protein degradation which should influence the course of numerous misfolding diseases by restricting the secretion of destabilized proteins. This endeavor is being carried out in collaboration with the laboratories of Dr. Balch (The Scripps Research Institute, Department of Cell Biology), Dr. Morimoto (Northwestern University), and Dr. Ron (New York University).
In keeping with the idea that normal physiology and pathology only differ slightly, we are also passionate about understanding the physical forces that enable protein folding in the cytoplasm and within the secretory pathway. We have utilized our expertise in chemical synthesis to introduce backbone modifications into the polypeptide chain to probe the role of H-bonding in both ground and transition state structures. As delineated in more detail in the summaries of the ongoing projects, we have learned that only a few H-bonds in a protein are energetically important for folding; the rest can be eliminated without significantly perturbing the acquisition of a functional fold.
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