| Biography: Dr. Huaibin Cai received his B.S. in Biology in 1991 from Peking University, Beijing, China and his Ph.D. in Neuroscience in 1999 from the Johns Hopkins University School of Medicine. He performed his postdoctoral training in the Division of Neuropathology, Department of Pathology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. He joined the NIA Laboratory of Neurogenetics in 2003 as an Investigator in the Computational Biology Section, Transgenics Unit. |
| Overview: Studying the pathogenic mechanisms of neurodegenerative diseases provides a unique opportunity not only to learn how the nervous system functions but also to develop effective mechanism-based treatments for these devastating illnesses. Development of animal models of these diseases will provide a very useful tool for examining the in vivo consequence of the underlying genetic mutations and for testing potential therapeutics. I am particularly interested in exploring the molecular pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) by using a combination of in vivo genetically engineered animal models and in vitro neurobiological approaches. |
| I. The Molecular Pathogenesis of AD: A wide variety of studies demonstrate that genetic mutations linked to Alzheimer's disease (AD) invariably increase the production and deposition of amyloid b (Ab) peptides, strongly supporting the idea that excessive Ab accumulation contributes to the pathogenesis of AD. Ab peptides are derived from amyloid precursor protein (APP) by endoproteolytic cleavages of BACE1 and g-secretase. Previously, we along with others have demonstrated that knockout of BACE1 in mice completely abolished the production of Ab. Recently, we have crossed these BACE1 knock mice with mutated APP and presenilin 1 (PS1) transgenic mice. We found that formation of Ab deposition, dystrophic neurites, as well as astrogliosis and microgliosis are completely prevented and cognitive impairments are fully rescued in these BACE1 null and APP/PS1 triple transgenic animals. These results strongly argue that BACE1 is a high priority therapeutic target for AD. However, even though the BACE1 knockout mice are viable and show no major pathological abnormalities, they do display subtle deficits in explorative activities and spatial learning and memory suggesting that BACE1 is somehow important for the normal functions of the brain. In order to learn more about the biological functions of BACE1, we propose to identify new substrates or related proteins for BACE1 other than APP family proteins by proteomics approaches. Because BACE1 protein is most abundant in neurons and we are more interested in studying the functions of BACE1 in the brain, we will define the proteins that display different expression levels in BACE1 KO neurons. Once we have validated candidates, we will examine their potential contributions to the normal functions of the nervous system and pathogenesis of AD. In addition, we are also engaged in identifying factors that regulate either the stability or b-secretase activity of BACE1. |
| Another issue has not been fully addressed in AD is how Ab peptides or their aggregates affect the functions of neurons. We plan to address this question by generating a line of conditional APP transgenic mice in which the APP transgene is selectively expressed by a subset of neurons. By comparing the morphological and physiological changes of wild-type to the adjacent mutant APP expressing neurons, we will be able to determine whether intracellular Ab acts in a cell autonomous or in a heterologous fashion to cause neuronal damages. |
| II. The Molecular Pathogenesis of Mutations in ALS2 and Dynactin: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron diseases. ALS also presents in rare cases as a juvenile-onset disease, and in a subset of these cases is inherited through mutations in the ALS2 gene. Genetic analyses suggest that this type of juvenile ALS is associated with the loss of ALS2 function, presumably its guanine-nucleotide-exchange factor (GEF) activities. We have generated the ALS2 knockout mice to model this type of motor neuron disease to address the following questions: what are the physiological function(s) of ALS2, and, how do mutations in ALS2 affect this function? In conjunction, we have also used yeast-two hybrid and co-immunoprecipitation approaches to identify the upstream or downstream signaling pathways in which ALS2 is involved. |
| Recently, a point mutation in Dynactin has been identified linked to motor neuron diseases. Dynactin is an intrinsic component of the protein complex mediating the intracellular transport. But, how the mutation in Dynactin particularly affects the protein or vesicle transport, or other functions in motor neurons is not clear. We also have no clue about why this mutation particularly causes the problems of motor neurons. We are in the middle of developing Dynactin mutation knockin and conditional knockout mouse models to address these questions. Because defects in axonal transportation have been found in many different kinds of neurodegenerative disease, these Dynactin mouse models will also shed light on some common pathogenic pathways lead to the neuronal degeneration. |
| III. The Molecular Pathogenesis of PD: Parkinson's disease is the second most common neurodegenerative disease. Recently, two recessive mutations in DJ-1 have been identified that are linked to the Parkinson's disease. There are many functions of DJ-1 that have been reported. But, how these functions are related to the normal function of dopaminergic neurons in the basal ganglia, or why the loss of DJ-1 specifically causes the death of this small population of neurons is not clear. We have modeled this genetic deficit in mice by knocking out DJ-1 gene. Meanwhile, we also have tried to define DJ-1 interacting proteins by yeast-two hybrid screening and other methods. |
