Fibroblast biomarkers of sporadic Parkinson's Disease and LRRK2 kinase inhibition

Smith, G. A. ORCID: https://orcid.org/0000-0003-4332-8383, Jansson, J., Rocha, E. M., Osborn, T., Hallett, P. J. and Isacson, O. 2016. Fibroblast biomarkers of sporadic Parkinson's Disease and LRRK2 kinase inhibition. Molecular Neurobiology 53 (8) , pp. 5161-5177. 10.1007/s12035-015-9435-4

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Humana Press
ISSN:	0893-7648
Date of Acceptance:	10 September 2015
Last Modified:	03 Nov 2022 09:51
URI:	https://orca.cardiff.ac.uk/id/eprint/106216

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