# Structural Studies of Lysosomal Storage Disease

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2021 · $382,405

## Abstract

PROJECT SUMMARY:
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-misfolding disease family,
which includes Alzheimer's, Parkinson's, and Huntington's diseases. Because lysosomal storage diseases are
generally caused by defects in single genes, the genetics of the diseases are simpler than in many human
diseases. Lysosomal storage diseases are very active targets of clinical research, with enzyme replacement
therapy, pharmacological chaperone therapy, substrate reduction therapy, bone marrow transplantation, gene
therapy, and stem cell therapy approaches either approved or under clinical investigation. Despite hundreds
of kilograms of recombinant enzymes produced industrially, the lack of basic knowledge about the
structure, ligand binding, catalysis, and stability of the clinical targets has slowed clinical progress.
For a lysosomal enzyme to function correctly, several critical steps must occur: the newly synthesized
polypeptide must translocate into the Endoplasmic Reticulum (ER), where it must fold correctly; it must be
post-translationally modified, allowing it to traffic through the Golgi apparatus to the lysosome; there, it must
have the correct catalytic machinery and sufficient stability to perform its enzymatic task. A failure in any of
these steps leads to loss of enzymatic function and subsequent disease progression. The understanding and
treatment of lysosomal storage diseases has been limited by lack of understanding of the molecular defects
that lead to disease symptoms. We will examine the basic biochemistry and biophysics at the root of lysosomal
storage diseases, which will propel further translational progress on the diseases.
To better understand the development of lysosomal storage diseases and other protein folding
diseases, we propose to study the folding, stability, and function of lysosomal enzymes. We have
developed methods for studying the biochemistry, biophysics, and cell biology of human lysosomal enzymes,
allowing us to interrogate each stage in the maturation of the enzymes, from synthesis to trafficking to function
in the lysosome. We are in the unique position to apply our expertise in the structural and cellular biology of
human glycoproteins to the problem of lysosomal storage disorders. We have determined the three-
dimensional structures of more human lysosomal enzymes than any other group, putting us in a unique
position to study the basic biochemistry and biophysics of the family of proteins. By directly tackling difficult
targets (human lysosomal enzymes are typical...

## Key facts

- **NIH application ID:** 10228565
- **Project number:** 5R01DK076877-14
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** Scott C. Garman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,405
- **Award type:** 5
- **Project period:** 2007-04-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228565

## Citation

> US National Institutes of Health, RePORTER application 10228565, Structural Studies of Lysosomal Storage Disease (5R01DK076877-14). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10228565. Licensed CC0.

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