Prenylation of Rho proteins - impact for neurodegeneration

Rac1

Isoprenoids and certain small Rho GTPases have been implicated in brain aging and neurodegenerative disorders in which current treatment options have been ineffective. Small Rho-GTPases are key regulators in neurogenesis, synapse formation and neuronal differentiation. Post-translational prenylation of small GTPases via transferases (FTase and GGTase I) is important for their localization in membranes, the site of their activation and function. Recent findings showed that regulation of the brain isoprenoids farnesyl (FPP)- and geranylgeranylpyrophosphate (GGPP) is altered in Alzheimer patients (Neurobiol Dis. 2009;35(2):251-7). Since Alzheimer`s disease is strongly associated with aging we tested herein the impact of aging on levels of the mevalonate pathway intermediates FPP and GGPP; levels of total and prenylated small Rho-GTPases; mRNA, protein and activity of GGTase I in cerebrum homogenates of young (2-months) and aged (23-months) C57/BJ6 mice. FPP and GGPP levels were significantly elevated (Mol Neurobiol. 2012; 46(1): 179-85). Currently, we investigate levels of Rho-GTPases Rac-1, RhoA and cdc42 in different brain fractions, e.g. membrane bound Rho-protein indicates prenylation of the proteins. Further, levels of GGTase I mRNA and protein levels,  Rho-GEF (guanine nucleotide exchange factor) Tiam1,  BDNF, and  TrkB receptor levels as well as synaptic markers are determined. The project is carried out by Ph.D. student Sarah Afshordel in cooperation with Prof. W. Gibson Wood, University of Minnesota, Minnapolis, USA.

References

Marschalek N, Albert F, Afshordel S, Meske V, Eckert GP, Ohm TG.
Geranylgeranyl pyrophosphate is crucial for neuronal survival but has no special role in Purkinje cell degeneration in Niemann Pick type C1 disease.
J Neurochem. 2015, 133(1):153-61

Afshordel S, Wood WG, Igbavboa U, Muller WE, Eckert GP. 
Impaired Geranylgeranyltransferase-I Regulation Reduces Membrane-Associated Rho Protein Levels in Aged Mouse Brain.
J Neurochem. 2014, 129(4):732-42.

Hooff GP, Wood WG, Hyun KJ, Igbavboa U, Ong WY, Muller WE, Eckert GP
Brain Isoprenoids Farnesyl Pyrophosphate and Geranylgeranyl Pyrophosphate are Increased in Aged Mice.
Mol Neurobiol. 2012, 46(1):179-85.

Hooff GP, Peters I, Wood WG, Müller WE, Eckert GP.
Modulation of cholesterol, farnesyl- and geranylgeranylpyrophosphate in neuronal SY5Y cells - impact for beta-amyloid production.
Mol Neurobiol. 2010, 41(2-3):341-50.

Eckert GP, Hooff GP, Igbavboa U, Strandjord DM, Volmer DA, Müller WE, Wood WG. Regulation of brain isoprenoids farnesyl and geranylgeranyl pyrophosphate is altered in male Alzheimer’s disease.
Neurobiol Disease. 2009, 35: 251-7.

Hooff GP, Volmer D, Wood WG, Müller WE, Eckert GP.
Isoprenoid quantitation in human brain tissue. A validated HPLC-fluorescence detection method for endogenous farnesyl- (FPP) and geranylgeranylpyrophosphate (GGPP).
Anal Bioanal Chem. 2008, 392: 673-80.



© Prof. Dr. Gunter P. Eckert 2018