Peter Lobel
 Professor

Hereditary neurodegenerative diseases. functional genomics. lysosomes. protein targeting

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.

Selected Publications

Kim KH, Sleat DE, Bernard O, Lobel P. (2009) Genetic modulation of apoptotic pathways fails to alter disease course in tripeptidyl-peptidase 1 deficient mice. Neurosci Lett. 453(1):27-30.

Sleat DE, Ding L, Wang S, Zhao C, Wang Y, Xin W, Zheng H, Moore DF, Sims KB, Lobel P. (2009) Mass spectrometry-based protein profiling to determine the cause of lysosomal storage diseases of unknown etiology. Mol Cell Proteomics. Apr 20. [Epub ahead of print]

Guhaniyogi J, Sohar I, Das K, Stock AM, Lobel P. (2009) Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis. J Biol Chem. 284(6):3985-97.

Lübke T, Lobel P, Sleat D. (2008) Proteomics of the lysosome. Biochim Biophys Acta. 1793(4):625-35.

Sun P, Sleat DE, Lecocq M, Hayman AR, Jadot M, Lobel P. (2008) Acid phosphatase 5 is responsible for removing the mannose 6-phosphate recognition marker from lysosomal proteins. Proc Natl Acad Sci U S A. 105(43):16590-5.

Kim KH, Pham C, Sleat DE, Lobel P. (2008) Dipeptidyl-peptidase I does not functionally compensate for the loss of tripeptidyl-peptidase I in the neurodegenerative disease late-infantile neuronal ceroid lipofuscinosis. Biochem J. 415(2):225-32.

Sleat DE, Della Valle MC, Zheng H, Moore DF, Lobel P. (2008) The Mannose 6-Phosphate Glycoprotein Proteome. J Proteome Res. 7(7):3010-21.

Chang M, Cooper JD, Sleat DE, Cheng SH, Dodge JC, Passini MA, Lobel P, Davidson BL. (2008) Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther. 16(4):649-56.

Sleat DE, El-Banna M, Sohar I, Kim KH, Dobrenis K, Walkley SU, Lobel P. (2008) Residual levels of tripeptidyl-peptidase I activity dramatically ameliorate disease in late-infantile neuronal ceroid lipofuscinosis. Mol Genet Metab. 94(2):222-33.

Dixit SS, Sleat DE, Stock AM, Lobel P. (2007) Do mammalian NPC1 and NPC2 play a role in intestinal cholesterol absorption? Biochem J. 408(1):1-5.

Qian M, Sleat DE, Zheng H, Moore D, Lobel P. (2008) Proteomics analysis of serum from mutant mice reveals lysosomal proteins selectively transported by each of the two mannose 6-phosphate receptors. Mol Cell Proteomics. 7(1):58-70.

Cabrera-Salazar MA, Roskelley EM, Bu J, Hodges BL, Yew N, Dodge JC, Shihabuddin LS, Sohar I, Sleat DE, Scheule RK, Davidson BL, Cheng SH, Lobel P, Passini MA. (2007) Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease. Mol Ther. 15(10):1782-8.

Xu S, Benoff B, Liou HL, Lobel P, Stock AM. (2007) Structural basis of sterol binding by NPC2, a lysosomal protein deficient in Niemann-Pick type C2 disease. J Biol Chem. 282(32):23525-31.

Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, Maxfield FR. (2007) Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell. 18(4):1490-6.

Sleat DE, Zheng H, Lobel P. (2007) The human urine mannose 6-phosphate glycoproteome.
Biochim Biophys Acta. Mar;1774(3):368-72.

Liou HL, Dixit SS, Xu S, Tint GS, Stock AM, Lobel P. (2006) NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols.
J Biol Chem. 281(48):36710-23.

Della Valle MC, Sleat DE, Sohar I, Wen T, Pintar JE, Jadot M, Lobel P. (2006) Demonstration of lysosomal localization for the mammalian ependymin-related protein using classical approaches combined with a novel density shift method. J Biol Chem. 281(46):35436-45.

Sleat DE. Wang Y. Sohar I. Lackland H. Li Y. Li H. Zheng H. Lobel P. (2006) Identification and validation of mannose 6-phosphate glycoproteins in human plasma reveals a wide range of lysosomal and non-lysosomal proteins. Mol Cell Proteomics. 5(10):1942-56.

Awano T. Katz ML. O'brien DP. Sohar I. Lobel P. Coates JR. Khan S. Johnson GC. Giger U. Johnson GS. (2006) A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Mol Genet Metab. 89(3):254-60.

Cheruku SR. Xu Z. Dutia R. Lobel P. Storch J. (2006) Mechanism of cholesterol transfer from the Niemann-Pick type C2 protein to model membranes supports a role in lysosomal cholesterol transport. J Biol Chem. 281(42):31594-604.

Passini MA. Dodge JC. Bu J. Yang W. Zhao Q. Sondhi D. Hackett NR. Kaminsky SM. Mao Q. Shihabuddin LS. Cheng SH. Sleat DE. Stewart GR. Davidson BL. Lobel P. Crystal RG. (2006) Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. J Neurosci. 26(5):1334-42.

Sleat DE. Zheng H. Qian M. Lobel P. (2006) Identification of sites of mannose 6-phosphorylation on lysosomal proteins. Mol Cell Proteomics. 5(4):686-701.

Awano T. Katz ML. O'Brien DP. Taylor JF. Evans J. Khan S. Sohar I. Lobel P. Johnson GS.(2006) A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis. Mol Genet Metab. 87(4):341-8.

Tian Y. Sohar I. Taylor JW. Lobel P. (2006) Determination of the substrate specificity of tripeptidyl-peptidase I using combinatorial peptide libraries and development of improved fluorogenic substrates. J Biol Chem. 281(10):6559-72.

Sleat DE. Lackland H. Wang Y. Sohar I. Xiao G. Li H. Lobel P. (2005) The human brain mannose 6-phosphate glycoproteome: a complex mixture composed of multiple isoforms of many soluble lysosomal proteins. Proteomics. 5(6):1520-32.

Sleat DE. Wiseman JA. El-Banna M. Kim KH. Mao Q. Price S. Macauley SL. Sidman RL. Shen MM. Zhao Q. Passini MA. Davidson BL. Stewart GR. Lobel P. (2004) A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration. J Neurosci. 24(41):9117-26.

Sleat DE. Wiseman JA. El-Banna M. Price SM. Verot L. Shen MM. Tint GS. Vanier MT. Walkley SU. Lobel P. (2004) Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc Natl Acad Sci U S A. 101(16):5886-91.

Friedland. N.. Liou. H.-L.. Lobel. P.. and Stock. A.M. (2003) Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease. Proc Natl Acad Sci U S A 100:2512-2517.

Lin. L.. Sohar. I.. Lackland. H.and Lobel. P. (2001). The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH. J Biol Chem 276:2249-2255

Lin. L. and Lobel. P. (2001) Production and characterization of recombinant human CLN2 protein for enzyme replacement therapy in late infantile neuronal ceroid lipofuscinosis. Biochem. J. 357:49-55.