The roles of kinases in familial Parkinson's disease.
The purpose of this mini-symposium is to discuss some of the inherited forms of Parkinson's disease (PD) in view of recent data suggesting that some of the proteins affect cellular signaling pathways. As an illustration, we shall focus on two different kinases associated with recessive and dominant forms of PD. Mutations in the mitochondrial kinase PTEN (phosphatase and tensin homolog)-induced kinase 1 (PINK1) are loss-of-function mutations in a normally neuroprotective protein. Loss-of-function mutations in model organisms have variable effects, from dramatic muscle and spermatid defects in Drosophila to more subtle neurophysiological abnormalities in mice. Several lines of evidence relate these to the action of a second gene for familial PD, parkin, an E3 ubiquitin ligase shown recently to have effects on Akt signaling. Mutations in leucine-rich repeat kinase 2 (LRRK2), a cytosolic kinase, are dominant and have the opposite effect of causing neuronal damage. The mechanism(s) involved are uncertain at this time because LRRK2 is a large and complex molecule with several domains. Increased kinase activity accounts for the action of at least some of the mutations, suggesting that hyperactive or misregulated kinase activity may lead to the damaging effects of LRRK2 in neurons. For both PINK1 and LRRK2, the following key question that needs to be answered: what are the physiological substrates that mediate effects in cells? Here, we will discuss some of the recent thinking about physiological and pathological roles for signaling in PD and how these may have therapeutic implications for the future.
Cookson
Mark R
MR
Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892-3707, USA. cookson@mail.nih.gov
Dauer
William
W
Dawson
Ted
T
Fon
Edward A
EA
Guo
Ming
M
Shen
Jie
J
D000818:Animals; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D010770:Phosphotransferases / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010770:Phosphotransferases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000099202:PTEN-Induced Putative Kinase; C495280:LRRK2 protein, human