The mevalonate- (MVA-) pathway is a crucial metabolic pathway for most eukaryotic cells, with cholesterol as its most recognized product. Cholesterol represents a strucural component of neuronal membranes.  

Cholesterol is also a precursor for neurosteroids which are produced in mitochondria after active import into the organell. Neurosteroidsynthesis links the mevalonate pathway to mitochondrial function. 

The mevalonate pathway also provides the cell with isoprenoids - another class of indispensable lipids. The short-chain isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) covalently attach to small GTPases, which act as molecular switches in various biochemical pathway. 

Synaptic dysfunction reprents another common hallmark of brain aging and neurodegenerative diseases.  The Rho family of small GTPases are one of the major regulators in synaptic plasticity, both in dendrite morphogenesis and stability as well as in growth cone motility. Prenylation is a requirement for their correct funtion. 

A tentative conclusion our recent results is that the regulation of isoprenoids is altered in brain aging and AD and such changes may alter protein prenylation and contribute to AD neuropathophysiology. Our latest un-published data indeed strongly indicate that Rho GPTases are mislocolized in brain ageing and neurodegeneration. 

Mevalonate neurosteroids

We are currently evaluating the potency of 7,8-dihydroxyflavone and of natural isoprenoids occurring in food, like tocotrienols or monoterpenes to interfere with the MVA-pathway and to modify Rho-GTPase signalling.

© Prof. Dr. Gunter P. Eckert 2018