Fatty aldehyde conjugates have been limited previously to phospholipids in the form of plasmalogen. We recently found a novel plasmal conjugate linked to galactosyl-sphingosine (psychosine) or to cerebroside through cyclic acetal linkage; these were termed """"""""plasmalopsychosine"""""""" (PLPS) and """"""""plasmalocerebroside'' (PLCER), respectively. PLPS induces neurotrophic arid anti-apoptotic effects in PC 12 cells through TrkA activation and prolonged enhancement of mitogen-activated protein kinase. PLPS induces similar effects in neuroblastoma Neuro2a cells independent from the effect of Nerve Growth Factor (NGF). Thus, PLPS mimics NGF effect. We propose to study: (1) structural requirements for neurotrophic and anti-apoptotic effects of PLPS; (2) possible enzymatic conversion of PLCER to PLPS, and tissue distribution pattern of PLPS and PLCER; (3) comparison of neurotrophic effects of PLPS with effects of known neurotrophins in various neuronal cell lines; (4) interactions of PLPS with neurotrophin receptors and """"""""glycosignaling domain"""""""" (GSD) which lead to activation of TrkA, p75NTR and other GSD-associated signal transducers; (5) anti-apoptotic activity of PLPS for normal, primary cultured neurons, (6) signal transduction pathways involved in the anti-apoptotic action of PLPS in cultured central and peripheral nervous system neurons, including kinase pathways (ERK, JNK, p38MAPK, AW PBK3, the pS3 tumor suppressor gene, members of the Bc1-2 family (Bc1-2, BC1-XL, Bax, Bad), caspases, [Ca2+]; free radical production and the mitochondrial function. Results of these studies may provide a basis for development of PLPS and its analogues as therapeutic reagents for neurodegenerative diseases and neuronal injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039560-02
Application #
6351905
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Mamounas, Laura
Project Start
2000-02-04
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
2
Fiscal Year
2001
Total Cost
$293,700
Indirect Cost
Name
Pacific Northwest Research Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98122
Hikita, Toshiyuki; Tadano-Aritomi, Keiko; Iida-Tanaka, Naoko et al. (2005) De-N-acetyllactotriaosylceramide as a novel cationic glycosphingolipid of bovine brain white matter: isolation and characterization. Biochemistry 44:9555-62
Tadano-Aritomi, Keiko; Hikita, Toshiyuki; Kubota, Masayuki et al. (2003) Internal residue loss produced by rearrangement of a novel cationic glycosphingolipid, glyceroplasmalopsychosine, in collision-induced dissociation. J Mass Spectrom 38:715-22
Hikita, Toshiyuki; Tadano-Aritomi, Keiko; Iida-Tanaka, Naoko et al. (2002) Cationic glycosphingolipids in neuronal tissues and their possible biological significance. Neurochem Res 27:575-81
Hikita, T; Tadano-Aritomi, K; Iida-Tanaka, N et al. (2001) A novel plasmal conjugate to glycerol and psychosine (""glyceroplasmalopsychosine""): isolation and characterization from bovine brain white matter. J Biol Chem 276:23084-91