The major goal of the proposed research is to understand the molecular basis of lysosomal storage diseases, a collection of more than 40 inherited metabolic disorders that affect approximately 1 in 7,700 births. Lysosomal storage disorders are caused by defects in single genes, where the loss of a functional enzyme in the lysosome leads to accumulation of substrate and the development of disease symptoms. Lysosomal storage diseases are some of the best-understood members of the larger protein folding disease family, which includes disorders including Alzheimer's, Parkinson's, and Huntington's diseases. For a lysosomal enzyme to function correctly, a series of critical events must occur: after synthesis of a polypeptide, it must translocate into the Endoplasmic Reticulum (ER), where it must fold correctly;it must be post-translationally modified, allowing it to traffi through the Golgi apparatus to the lysosome;there, it must have the correct catalytic machinery and the stability to perform its enzymatic task. If there is a failure in any of these steps, the lysosomal enzyme will not function and disease will develop. Progress in the understanding and treatment of lysosomal storage diseases has been limited by the complexity of the pathway: a lysosomal storage disorder can develop due to failure of folding of the protein, failure of trafficking of the protein to the lysosome, or failure of the enzyme to function in the lysosome, etc. In order to better understand the development of lysosomal storage diseases and other protein folding diseases, we propose to study the folding, trafficking, and function of lysosomal enzymes. We propose to improve understanding of protein folding diseases by studying the molecular mechanism of pharmacological chaperoning in Fabry and Schindler diseases, by studying the structural basis of mucopolysaccharidosis, and the study of the structural basis of lysosomal trafficking. We propose to further knowledge and treatment of human disease by directly tackling difficult targets: human lysosomal enzymes, which are typically heavily glycosylated and otherwise post-translationally modified multimers.

Public Health Relevance

Lysosomal storage diseases are inherited metabolic diseases caused by a single defect in a single gene. We study these inherited diseases by discovering the three-dimensional shape of the proteins that are damaged in the diseases. This allows us to better understand how the diseases progress and how to better treat them.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Macromolecular Structure and Function B Study Section (MSFB)
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Leschek, Ellen W
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University of Massachusetts Amherst
Schools of Arts and Sciences
United States
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Germain, Dominique P; Brand, Eva; Burlina, Alessandro et al. (2018) Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study. Mol Genet Genomic Med :
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