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The Kelly Group Research

Our major goal is to understand the molecular mechanisms of protein folding and misfolding in a test tube, and in the cytoplasm and secretory pathway of mammalian cells. To accomplish this, we employ cell biological, spectroscopic, and biophysical approaches, in combination with chemical synthesis. The latter is being utilized to discover small molecules that manipulate protein folding and misfolding at the protein level and systems biology level in mammals. Besides understanding protein misfolding diseases, we also aim to develop new small-molecule therapeutic strategies against these neurodegenerative disorders.

Introduction:

Protein misfolding diseases are becoming increasingly common as the population ages and as we improve the diagnosis of these pathologies. The World Health Organization estimates that by 2040, neurodegenerative diseases will overtake cancer as the second leading cause of death behind heart disease. 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 of the misfolded-prone protein 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 pharmacologic chaperones that stabilize the native state in the ER enabling the folding and trafficking of these variant proteins, as well as small molecules that transcriptionally reprogram the proteostasis network of the ER, enabling folding and trafficking.

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 structure appears to cause these degenerative diseases based on genetic and biochemical evidence. The formation of such aggregates causes devastating neurodegenerative diseases including Alzheimer’s disease and Parkinson’s 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 and Tau protein that 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 used to impose kinetic stabilization on the native state of transthyretin, precluding misfolding and amyloid formation and thus slowing neurodegenerative disease progression. We also seek small molecules that activate autophagy, influence the unfolded protein response (by perturbing chaperone distribution, concentration, and folding enzyme activities) or restrict the secretion of destabilized proteins, for example. This endeavor is being carried out in collaboration with the laboratories of Dr. Wiseman (The Scripps Research Institute, Department of Molecular Medicine), Dr. Encalada (The Scripps Research Institute, Department of Molecular Medicine), and Dr. Yates (The Scripps Research Institute, Department of Molecular Medicine).

In keeping with the idea that normal physiology and pathology only differ slightly, we are also passionate about understanding the physical forces and biology that enable protein folding in the cytoplasm and within the secretory pathway.

 

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Introduction

Transthyretin amyloid diseases

Development of an Inverse Drug Discovery Platform

Discovery of novel small-molecule activators of autophagy for the treatment of Parkinson's and other neurodegenerative diseases

Discovering small molecule regulators of the proteostasis network that function through stress-responsive signaling pathway activation

The enhanced aromatic sequon and the energetics of N-glycosylation

β-Sheet folding

Restoration of enzyme homeostasis in lysosomal storage diseases