The hallmark of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis is the derangement of the cytoskeleton of the neuron and deposition of cytoskeletal proteins, usually in a highly phosphorylated form, as filamentous deposits. The composition of these deposits differs among the diseases but where examined, they always contain neurofilament (NF) subunits. Research into this manifestation of neurodegenerative diseases has been slow because human neurofilaments are unique and different from those of other species in several important regards. Furthermore, many aspects of neurofilament assembly and function are best studied in the neuron--a large post-mitotic cell. In the absence of an adequate neuron cell culture system cell culture system, laboratory animals are the experimental systems of choice. The focus of this project is the study of intraneuronal assembly. of the neurofilament networks and the involvement of neurofilament networks in neurodegenerative diseases. Specifically we propose to explore the differences in homopolymerization and assembly of human and mouse NF-L. Our previous work indicates a striking difference between the assembly capabilities of the human and rodent NF-L subunits and we will now examine the ability of human NF-L to homopolymerize in neurons in the absence of other NF subunits. We will examine the role of serine 55 in homopolymerization of NF-L and will investigate the consequences of mutating SER/55 to amino acids which cannot be phosphorylated. Truncations of the mouse NF-M will be prepared and tested for their ability to stabilize the NF-L and how their incorporation effects NF spacing and axonal caliber. We will test the hypothesis that char repulsion provided by the phosphates on the NF- H carboxy terminus are important in determining NF spacing. With regard to the involvement of NF networks in neurodegenerative diseases, we will characterize by microscopy mice in which human NF networks replace the endogenous networks and compare young and old (1+ years) animals. We will introduce transgenes encoding the Ab peptide into these mice to assess whether increased levels of Ab or amyloid deposits will elicit intraneuronal neurofibrillary tangles in these """"""""humanized"""""""" mice. We will investigate the pathology seen in NF-M/H double null mutant mice and characterize the IF-like filaments found in these mice that should lack all neurofilaments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005138-18
Application #
6446893
Study Section
Project Start
2001-04-15
Project End
2002-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
18
Fiscal Year
2001
Total Cost
$196,218
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
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