The neurovirulent ecotropic murine retrovirus, CasBrE, causes progressive, non-inflammatory spongiform neurodegenerative disease in motor areas from the spinal cord through the neocortex when inoculated into susceptible neonatal mice. This infection leads to hind limb paralysis, wasting and eventual death. The neuropathology caused by this retrovirus is highly reminiscent of the changes which occur in human prion-associated Spongiform encephalopathy and involves CNS motor system components which are specifically targeted in amyotrophic lateral sclerosis (ALS) and tropical spastic paraparesis (HAM-TSP). Thus, the CasBrE retrovirus-induced neurodegenerative disease provides an appealing system for dissecting mechanisms by which pathologic changes in motor system neurons can occur. The goal of this proposal is to understand the specific molecular pathways by which retroviruses corrupt motor system function and motor neuron viability. Genetic mapping analysis of CasBrE indicates that neurovirulence determinants map to the env gene. The investigators in vivo studies indicate that neurodegeneration induced by CasBrE is specifically mediated through late virus replication events in microglial cells. Furthermore, in vitro experiments indicate that microglial infection is defective, which correlates with altered env synthesis in these cells. Finally, CasBrE env binding to its receptor (MCAT-1) completely blocks cationic amino acid transport. To understand the relationship between env, microglial infection, and neurologic disease the Specific Aims of this proposal are (1) to identify the molecular features of CasBrE env which are responsible for receptor binding, amino acid transport inhibition, altered envelope processing, and defective viral replication in vitro and (2) to use the in vitro results to specifically reconstitute in the brain those viral replication events that are essential for inducing neurodegeneration. By using novel transplantation and chimeric approaches for expressing genes in the CNS, they can reconstitute limited aspects of the CasBrE replication cycle and analyze neurodegenerative disease in the absence of an ongoing retroviral infection. The procedures employed should provide insight into the specific mechanisms of CasBrE-induced retroviral neurodegeneration and will have broad applicability toward understanding the role that microglia play in motor and non-motor neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS037614-02
Application #
2839443
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Heemskerk, Jill E
Project Start
1997-12-01
Project End
2002-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Northeast Ohio Medical University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Rootstown
State
OH
Country
United States
Zip Code
44272