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.