Isoprenoids, small GTPases and Alzheimer's disease

Gero P. Hooff, W. Gibson Wood, Walter E. Müller, Gunter P. Eckert

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

The mevalonate pathway is a crucial metabolic pathway for most eukaryotic cells. Cholesterol is a highly recognized product of this pathway but growing interest is being given to the synthesis and functions of isoprenoids. Isoprenoids are a complex class of biologically active lipids including for example, dolichol, ubiquinone, farnesylpyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Early work had shown that the long-chain isoprenoid dolichol is decreased but that dolichyl phosphate and ubiquinone are elevated in brains of Alzheimer′s disease (AD) patients. Until recently, levels of their biological active precursors FPP and GGPP were unknown. These short-chain isoprenoids are critical in the post-translational modification of certain proteins which function as molecular switches in numerous signaling pathways. The major protein families belong to the superfamily of small GTPases, consisting of roughly 150 members. Recent experimental evidence indicated that members of the small GTPases are involved in AD pathogenesis and stimulated interest in the role of FPP and GGPP in protein prenylation and cell function. A straightforward prediction derived from those studies was that FPP and GGPP levels would be elevated in AD brains as compared with normal neurological controls. For the first time, recent evidence shows significantly elevated levels of FPP and GGPP in human AD brain tissue. Cholesterol levels did not differ between AD and control samples. One obvious conclusion is that homeostasis of FPP and GGPP but not of cholesterol is specifically targeted in AD. Since prenylation of small GTPases by FPP or GGPP is indispensable for their proper function we are proposing that these two isoprenoids are up-regulated in AD resulting in an over abundance of certain prenylated proteins which contributes to neuronal dysfunction.

Original languageEnglish (US)
Pages (from-to)896-905
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1801
Issue number8
DOIs
StatePublished - Aug 2010

Bibliographical note

Funding Information:
This work was supported by the Alzheimer Forschung Initiative e.V. ( grant AFI #08823 ), the National Institutes of Health, National Institute on Ageing (grants AG23524 and AG18357 ) and the Department of Veterans Affairs .

Keywords

  • Cholesterol
  • Farnesylpyrophosphate
  • Geranylgeranylpyrophosphate
  • Rho
  • Small GTPases
  • Synaptic plasticity

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