LRRK2 Expression Is Deregulated in Fibroblasts and Neurons from Parkinson Patients with Mutations in PINK1.

Azkona, GarikoitzLópez de Maturana, RakelDel Rio, PatriciaSousa, AmayaVazquez, NereaZubiarrain, AmaiaJimenez-Blasco, DanielBolaños, Juan PMorales, BlasAuburger, GeorgArbelo, José MatiasSánchez-Pernaute, Rosario2023-01-252023-01-252016-12-14http://hdl.handle.net/10668/10680Mutations in PINK1 (PARK6), a serine/threonine kinase involved in mitochondrial homeostasis, are associated with early onset Parkinson's disease. Fibroblasts from Parkinson's disease patients with compound heterozygous mutations in exon 7 (c.1488 + 1G > A; c.1252_1488del) showed no apparent signs of mitochondrial impairment. To elucidate changes primarily caused by lack of functional PINK1, we over-expressed wild-type PINK1, which induced a significant downregulation of LRRK2 (PARK8). Indeed, we found that LRRK2 protein basal levels were significantly higher in the mutant PINK1 fibroblasts. To examine the interaction between the two PARK genes in a disease-relevant cell context, we generated induced pluripotent stem cell (iPSC) lines from mutant, carrier and control fibroblasts by lentiviral-mediated re-programming. Efficiency of neural induction and dopamine differentiation using a floor-plate induction protocol was similar in all genotypes. As observed in fibroblasts, PINK1 mutant neurons showed increased LRRK2 expression both at the RNA and protein level and transient over-expression of wild-type PINK1 efficiently downregulated LRRK2 levels. Additionally, we confirmed a dysregulation of LRRK2 expression in fibroblasts from patients with a different homozygous mutation in PINK1 exon 4, c.926G > A (G309D). Thus, our results identify a novel role of PINK1 modulating the levels of LRRK2 in Parkinson's disease fibroblasts and neurons, suggest a convergent pathway for these PARK genes, and broaden the role of LRRK2 in the pathogenesis of Parkinson's disease.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/LRRK2PINK1Parkinson diseaseiPSCDown-RegulationFemaleFibroblastsHumansInduced Pluripotent Stem CellsLeucine-Rich Repeat Serine-Threonine Protein Kinase-2MaleMiddle AgedMutationNeuronsParkinson DiseaseProtein KinasesLRRK2 Expression Is Deregulated in Fibroblasts and Neurons from Parkinson Patients with Mutations in PINK1.research article27975167open access10.1007/s12035-016-0303-71559-1182PMC5808058https://link.springer.com/content/pdf/10.1007%2Fs12035-016-0303-7.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808058/pdf