MAPK-pathway activity, Lrrk2 G2019S, and Parkinson's disease.
The 6055G>A mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in a G2019S substitution in the mixed-lineage kinase domain of Lrrk2, causing autosomal dominant Parkinson's disease (PD). We hypothesized the mutation alters cellular mitogen-activated protein kinase (MAPK) signalling cascades, and might be detectable in tissues other than in the brain. We therefore compared total levels and activation of the signalling proteins Src, HSP27, p38 MAPK, JNK, and ERK, in extracts of leukocytes isolated from patients with PD carrying the G2019S mutation, healthy mutation carriers, patients with idiopathic PD, and healthy controls. Phosphorylation of Src, HSP27, and JNK was reduced significantly in cell extracts from patients with G2019S-associated PD compared to healthy controls. Similarly, phosphorylation was reduced significantly in Src and HSP27 in the group of healthy carriers of the mutation, as well as in patients with idiopathic PD. Significant reductions in total Src were also observed in these three groups compared to the controls. The results of this pilot project therefore indicate significant alterations in key signalling proteins in leukocytes from patients with PD, and were most pronounced in G2019S-associated PD. Changes in MAPK-signalling may thus be common to PD pathophysiology, regardless of aetiology. Such changes may also be shown in blood samples during the preclinical stage of LRRK2-associated PD, which could be particularly important for the development of neuroprotective strategies to delay onset, or slow progression of PD.
White
Linda R
LR
Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. linda.white@ntnu.no
Toft
Mathias
M
Kvam
Sylvia N
SN
Farrer
Matthew J
MJ
Aasly
Jan O
JO
D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005998:Glycine / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009664:Norway; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012694:Serine / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D018709:Statistics, Nonparametric
D012694:Serine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D005998:Glycine