title: Fibroblast Biomarkers of Sporadic Parkinson's Disease and LRRK2 Kinase Inhibition.
abstract: It has been uncertain whether specific disease-relevant biomarker phenotypes can be found using sporadic Parkinson's disease (PD) patient-derived samples, as it has been proposed that there may be a plethora of underlying causes and pathological mechanisms. Fibroblasts derived from familial PD patients harboring leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), and Parkin mutations show clear disease-relevant mitochondrial phenotypes, which are exacerbated under conditions of pharmacological stress. We utilized fibroblasts derived from non-familial sporadic PD patients (without LRRK2 mutations) or LRRK2 mutation carriers to directly compare the cellular phenotypes during and after mitochondrial stress. We then determined the effects of pharmacological LRRK2 kinase inhibition using LRRK2-in-1. We found that there were two distinct populations of sporadic PD patient-derived fibroblast lines. One group of sporadic PD lines was highly susceptible to valinomycin-induced mitochondrial depolarization, emulating the mutant LRRK2 phenotype. These lines showed elevated mitochondrial superoxide/ nitric oxide levels, displayed increased mitochondrial and lysosome co-localization, and an increased rate of mitochondrial collapse, which corresponded with changes in mitochondrial fission and fusion proteins. The application of LRRK2-in-1 reversed decreased levels of mitochondrial and lysosome co-localization and partially restored mitochondrial network associated proteins and the mitochondrial membrane potential in the fibroblasts. This study identifies novel mitochondrial biomarkers in sporadic PD patient-derived fibroblast lines, which could be used as preclinical tools in which to test novel and known neuroprotective compounds.
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital/ Harvard Medical School, 115 Mill Street, Belmont, 02478, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Smith
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital/ Harvard Medical School, 115 Mill Street, Belmont, 02478, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jansson
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital/ Harvard Medical School, 115 Mill Street, Belmont, 02478, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Rocha
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital/ Harvard Medical School, 115 Mill Street, Belmont, 02478, USA.
authors.forename: T
authors.initials: T
authors.lastname: Osborn
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital/ Harvard Medical School, 115 Mill Street, Belmont, 02478, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Hallett
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital/ Harvard Medical School, 115 Mill Street, Belmont, 02478, USA. isacson@hms.harvard.edu.
authors.forename: O
authors.initials: O
authors.lastname: Isacson
mesh_terms: D001570:Benzodiazepinones / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism*; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D013312:Stress, Physiological / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014634:Valinomycin / Q000494:pharmacology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D001570:Benzodiazepinones; D015415:Biomarkers; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D011494:Protein Kinases; D011743:Pyrimidines; D044767:Ubiquitin-Protein Ligases; D014634:Valinomycin; D000099202:PTEN-Induced Putative Kinase; C582847:LRRK2-IN1; C111567:parkin protein
keywords: Biomarkers; Fibroblasts; LRRK2; Mitochondria; Parkin; Sporadic Parkinson’s disease