Our laboratory studies lysosomes and associated human. Lysosomes are organelles found in all eukaryotic cells that contain many different proteases. glycosidases. lipases and other hydrolytic enzymes. The lysosome functions as the cell's recycling compartment. breaking down complex biological macromolecules into simple components. The importance of these organelles is underscored by the existence of over thirty human genetic disorders (e.g.. Tay-Sachs disease) where loss of function of a single lysosomal enzyme can lead to severe health problems including neurodegeneration. progressive mental retardation. and early death.
1. Disease discovery. Our laboratory has pioneered novel protein-based approaches to identify the molecular basis for lysosomal storage disorders of unknown etiology and have used these to identify the disease genes in late infantile neuronal ceroid lipofuscinosis (LINCL) and Niemann-Pick Type C2 disease NPC2). We are currently using this and other approaches to determine the causes of other hereditary lysosomal diseases.
2. Medical applications. One tragic aspect of lysosomal neurodegenerative diseases is that they are often misdiagnosed and families can spend years trying to determine the cause of their child's progressive decline. Our laboratory has developed DNA and enzyme based assays for LINCL that allow carrier screening. diagnosis. and prenatal testing. In addition. we are developing knockout mice to produce small animal models for LINCL and NPC2 that will allow detailed studies of disease pathophysiology and evaluation of neuroprotective. enzyme replacement. and gene therapies.
3. Functional genomics/proteomics. With the sequencing of the human genome approaching completion. one pressing challenge is to determine the function of the encoded proteins. Knowledge of the subcellular location of a protein provides critical information that can help decipher its function. Our goal is to identify the spectrum of lysosomal proteins and to use this information to investigate their biochemistry and function in normal and disease processes.
4. Molecular cell biology of protein targeting. A fundamental problem faced by eukaryotic cells is how to target different types of proteins from their site of biosynthesis to their final destinations. Our laboratory is working to understand the molecular basis for targeting of lysosomal enzymes to the lysosome.