The Role of MyD88-5 in the Central Nervous System

Aiho Ding, Ph.D.

Weill Medical College of Cornell University

Funded in September, 2005: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . FINDINGS . SELECTED PUBLICATIONS .

LAY SUMMARY

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The Role of MyD88-5 in the Central Nervous System

This animal study will explore whether an "adaptive" protein called "MyD88-5" is a possible link between the brain and the immune system. The study will examine the role of MyD88-5 in signaling cells to mount an inflammatory response against invading bacteria. The investigators will also explore whether misregulated signaling of the protein results in the onset and progression of an animal model of Parkinson's disease.

The MyD88-5 protein is found almost exclusively in neurons in the brain. It has been detected in few other tissues. The MYD88-5 family proteins are known to pass signals from invading microorganisms to cells, stimulating innate immune responses against invaders. Importantly, the investigators hypothesize, MyD88-5 also may regulate the brain's inflammatory response to brain infections. It is also possible, the researchers suggest, that when too little MyD88-5 is present, brain neurons function abnormally, causing unregulated inflammatory signals, which, in turn, could affect the onset and progression of Parkinson's disease. The researchers will test their two hypotheses concerning the possible roles of MyD88-5 in mice that have been engineered to contain different copies of the MyD88-5 protein, or that lack the protein entirely.

Significance: This study may open new avenues of research concerning the brain's inflammatory response to bacterial infection and the protein's potential for contributing to Parkinson's disease when the protein is misregulated.

ABSTRACT

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The Role of MyD88-5 in the Central Nervous System

Myeloid differentiation primary-response protein 88 (MyD88) is the prototype of a family of cytosolic proteins that share a conserved intracellular TLR/IL-1 receptor domain (TIR). In humans, five MyD88-like molecules have been annotated, although only four have been characterized. These proteins serve as signal adaptors for IL-1 and IL-18 receptors, as well as Toll-like receptors (TLRs), which sense unique repetitive structures in microorganisms and mediate innate immune responses against invading pathogens. Mice with single MyD88 knockouts show enhanced susceptibilities to microbial pathogens and emphasize the importance of MyD88 family of proteins in host defense. We have cloned MyD88-5, an 80 kDa cytosolic protein with a C-terminal TIR domain, an N-terminal heat/armadillo-motif and two sterile alpha-domains. Unlike the broad tissue distribution of other MyD88s, however, MyD88-5 is preferentially expressed in the brain and undetected in most other tissues. This restricted neural expression pattern suggests that MyD88-5 represents a new link between innate immunity and neuronal function.

The goal of the present application is to study the role of MyD88-5 in the central nervous system (CNS). We are in the process of generating (i) MyD88-5 transgenic mice expressing either MyD88-5/GFP fusion protein or GFP only under its native promoter and enhancer using a bacterial artificial chromosome (BAC) transgenesis system, and (ii) MyD88-5 knockout mice by homologous recombination. These mice will be used to study the regulation of MyD88-5 expression in the brain during development and bacterial infection.

We will also examine the effects of MyD88-5 on CNS development during embryogenesis, adult neuronal motor function and learning/memory ability, brain inflammatory cytokine expression profiles in pneunococcal meningitis. Next, we will cross-breed MyD88-5 knockout mice with a Parkinson's disease (PD) model PINK1-/-. These mice will be used to dissect the effect of MyD88-5 on the onset and progression of Parkinson's disease phenotypes.

The results of these studies will elucidate the role of MyD88-5 in the brain, provide new targets for intervention of neurodegenerative diseases and, more generally, broaden our understanding of biology of TLR/MyD88-like proteins.

INVESTIGATOR BIOGRAPHIES

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Aiho Ding, Ph.D.

A graduate of Beijing University in China, Aihao Ding, Ph.D., is a Professor in the Department of Microbiology and Immunology, the Weill Medical College of Cornell University. She came to America in 1980 to enter the graduate program at the Downstate Medical Center of SUNY, where she obtained a Ph.D. in biochemistry in 1984. Following her postdoctoral training at Rockefeller University under the direction of Dr. Carl Nathan, Dr. Ding accepted a junior faculty position at Cornell Medical College in 1986, first at the Department of Medicine, and then at the Department of Microbiology and Immunology. The main focus of her research interests is in macrophage responses to host and microbial products. Dr. Chenjian Li, Ph.D., is an Assistant Professor and head of the Laboratory of Molecular Genetics and Neurodegenerative Disease in the Department of Neurology and Neuroscience at Weill Medical College of Cornell University. He received his undergraduate education at Beijing University and medical training in Peking Union Medical College. He obtained his Ph.D. in molecular genetics from Purdue University. Subsequently, he continued his training in the laboratories of Dr. Bruce McEwen and Dr. Nathaniel Heintz at Rockefeller University. Currently, Dr. Li's laboratory is focused on generating and analyzing mouse models of neurodegenerative diseases such as Huntington's disease and Parkinson's disease. In studying mouse models, biochemical, cellular, histological, and behavioral analyses are applied. He is also developing new technology for brain research.

FINDINGS

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MYD88-5 (SARM) is a newly discovered member of the MYD88 family, a group of cytosolic proteins that play an important role in innate immune responses.  To understand the role of MYD88-5 in the development and functional integrity of the central nervous system, we generated MYD88-5 knockout mice and MYD88-5 transgenic mice.  We found that this protein has a minimal role in the brain development because mice lacking MYD88-5 exhibited no detectable abnormality in the brain tissue under normal conditions.  However, when there is a stress, MYD88-5 knockout mice seemed to cope better than normal mice.  For example, brain tissues from MYD88-5 knockout mice were resistant to damages caused by depletion of oxygen and glucose, a condition often encountered during stroke.  Even 30 minutes of exposure to a medium containing little oxygen and glucose can kill neurons from normal nice. 

MYD88-5 knockout mice were also resistant to an acute regimen of a neurotoxin, MPTP, which induces Parkinson’s disease-like symptoms in humans and experimental animals.  Neuronal loss was greatly reduced in MYD88-5 knockout mice compared to normal mice after MPTP treatment.  We further discovered that MYD88-5 participated in neuronal stress responses by affecting another protein called JNK3.  MYD88-5 appears to have a role in JNK3, signaling cascade induced by stresses.  Right now we are studying why loss of MYD88-5 protects mice from stress-induced neurotoxicity and whether there is a way to inhibit MYD88-5 normal function and protect mice from other neuronal injuries.

SELECTED PUBLICATIONS

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Kim, Y., P. Zou, L. Qian, J. Chuang, J. Lee, C. Li, C. Iadecola, C. Nathan and A. Ding. MYD88-5 links mitochondria, nicrotubules and JNK3 in neurons and regulates neuronal survival. J. Exp. Med., 204:2063-2074, 2007.