X-linked adrenoleukodystrophy (XALD) is a progressive neurodegenerative disorder with two main clinical phenotypes, a rapidly fatal, childhood- onset cerebral form and a milder, slowly progressive adult-onset peripheral neuropathy. Biochemically, decreased very long-chain fatty acid (VLCFA) activation by very long-chain acyl-CoA synthetase (VLCS) in peroxisomes results in impaired VLCFA beta-oxidation and subsequent elevation of tissue VLCFA levels. ALDP, the product of the gene defective in XALD, resembles ATP-binding cassette transmembrane transporter proteins and is not a VLCS. We hypothesize that disruption of a VLCS/ALDP interaction is responsible for loss of VLCS activity, and thus XALD. We have identified a new family of proteins that includes VLCS, and have cloned six human, mouse and yeast VLCS genes and homologs. One objective of this proposal is to identify the requirements and components of the peroxisomal VLCFA activation system and to determine how this process is disrupted in XALD. A second objective is to characterize the members of this newly described protein family with respect to both XALD and VLCFA metabolism. To accomplish this, VLCFA activation will be studied in yeast and mouse model systems. The yeast VLCS (Fatlp) will be characterized and other enzymes with VLCS activity will be identified. Gene disruption strategies will be used both to elucidate the components of VLCFA activation in yeast and to create a vehicle for expression of homologous mammalian genes. The remaining mouse and human VLCSs will be cloned and their gene products characterized. The mouse model of XALD created by targeted gene disruption will then be used to investigate the effects of ALDP absence on VLCS activity, tissue expression, and subcellular distribution. Furthermore, to determine whether VLCS tissue expression could affect phenotypic expression in XALD, the various mouse and human VLCS genes will be mapped and their map positions compared to emerging chromosomal locations of candidate XALD modifier genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS037355-01A1
Application #
2757964
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Sheridan, Philip
Project Start
1999-02-01
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
DUNS #
167202410
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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