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Azkona Et Al. 2015 Increased LRRK2 in PINK1 Mutants Azkona et al. 2015 Increased LRRK2 in PINK1 mutants Lack of functional PINK1 is accompanied by increased LRRK2 levels in Parkinson disease fibroblasts and iPSC-neurons Garikoitz Azkona1,2#, Rakel López de Maturana2, Patricia Del Rio2, Amaya Sousa2, Nerea Vazquez2, Amaia Zubiarrain2, Dani...3,4, Juan Pedro Bolaños3,4, José Matias Arbelo5, Rosario Sánchez-Pernaute2* 1. Animal Model Unit, Inbiomed, San Sebastian (Spain) 2. Laboratory of Stem Cells and Neural Repair, Inbiomed, San Sebastian (Spain) 3. Institute of Functional Biology and Genomics (IBFG), University of Salamanca- CSIC, Salamanca (Spain) 4. Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, Salamanca (Spain) 5. Parkinson’s and Movement Disorders Unit. Department of Neurology. Hospital Universitario Insular de Gran Canaria. Las Palmas de Gran Canaria (Spain) # Present address: Animal Research Facility. Scientific and Technological Centers. University of Barcelona, Barcelona (Spain). * Corresponding author Rosario Sánchez-Pernaute Laboratory of Stem Cells and Neural Repair, Inbiomed P. Mikeletegi, 81; 2009 San Sebastian (Spain) Tlf: +34 943 309 064 Ext. 225 Fax: +34 943 308 022 E-mail: [email protected] RunningTitle: Increased LRRK2 in PINK1 mutant cells 1 Azkona et al. 2015 Increased LRRK2 in PINK1 mutants Abstract Mutations in PINK1 (PARK6), a serine/threonine kinase involved in mitochondrial homeostasis, are associated with early onset Parkinson disease. Analysis of fibroblasts from two PINK1 Parkinson’s disease patients (c.1488+1G >A; c.1252_1488del) showed subtle signs of mitochondrial impairment and compensatory changes in fusion and fission proteins to maintain mitochondrial network morphology. To elucidate changes primarily caused by lack of functional PINK1 we first over-expressed wild-type PINK1, which induced minor adjustments in the expression of fusion and fission genes but a significant down-regulation of LRRK2 (PARK8). Furthermore, we found that, under basal conditions, LRRK2 protein levels were significantly higher in the mutant PINK1 fibroblasts. Lentiviral-mediated silencing of LRRK2 modified the expression of genes involved in mitochondrial dynamics in control and carrier cells (c.1488+1G >A) but was ineffective in cells from the PINK1 Parkinson’s disease patients, suggesting that LRRK2 effect on mitochondrial homeostasis is mediated by functional PINK1 kinase activity. To further examine this interaction we generated induced pluripotent stem cell lines (iPSC) from mutant, carrier and control fibroblasts by lentiviral-mediated reprogramming. Neural induction and dopamine differentiation were similar in all genotypes. As observed in fibroblast, PINK1 mutant neurons showed increased LRRK2 expression both at the RNA and protein level. Finally, we investigated the expression of alpha-synuclein in iPSC-derived neural progenitors and neurons but these were not increased in the PINK1 mutant neurons. Our results identify a novel role of PINK1 modulating the levels of LRRK2 in Parkinson’s disease patient fibroblasts and iPSC- derived neurons and suggest a convergent pathway for these two PARK genes in the pathogenesis of Parkinson’s disease. 2 Azkona et al. 2015 Increased LRRK2 in PINK1 mutants Keywords: Parkinson disease, dopamine, neurodegeneration, mitochondria, iPSC, PARK genes, PINK1, LRRK2, alpha synuclein Abbreviations: 3 Azkona et al. 2015 Increased LRRK2 in PINK1 mutants Introduction Parkinson’s disease is the second most common neurodegenerative disease (de Rijk et al., 1995), and results from the progressive loss of dopamine neurons in the substantia nigra pars compacta (Lees et al., 2009). Although Parkinson’s disease is a complex, multifactorial and largely sporadic disease, rare familiar monogenic forms have been correlated to specific genetic mutations (Farrer, 2006), providing the opportunity to identify causes of parkinsonism and study new pathways in cell biology. An early-onset recessive Parkinson’s disease gene was found on chromosome 1 at the PARK6 locus in a large Italian pedigree (Valente et al., 2002). The 8-exon PARK6 gene encodes a 581 amino acid protein, phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) with a C-terminal serine/threonine kinase domain and a mitochondrial targeting sequence at the N terminus (Valente et al., 2004). Parkinson’s disease related mutations cluster around the kinase domain and compromise kinase function or protein stability, so the phenotype is thought to result from a loss of function. Besides, the mitochondrial localization supported its involvement in mitochondrial dysfunction observed in Parkinson’s disease. ADD a sentence about this family ?. Dopamine neurons are especially dependent on PINK1, which protects againts stress- induced mitochondrial dysfunction (Valente et al. 2004). PINK1 plays an important role in mitochondrial fidelity in Parkinson’s disease (for review see, (Pickrell and Youle, 2015). Upon mitochondrial damage PINK1 is stabilized on the outer membrane of the mitochondria and recruits the E3 ubiquitin (Ub) ligase Parkin (PARK2) from the cytosol to mediate mitophagy (Matsuda et al., 2010; Vives-Bauza et al., 2010) thus, PINK1/Parkin signaling pathway controls mitochondrial quality. The proper function of the PINK1/Parkin pathway requires PINK1’s kinase activity (Yu et al., 2011). However, despite the interest in the role of PINK1 in mitophagy, it appears that this pathway is not 4 Azkona et al. 2015 Increased LRRK2 in PINK1 mutants modified by PINK1 mutations under physiological conditions, i.e. in systems with endogenous expression (Morais et al., 2014; Rakovic et al., 2013). Besides its role in mitophagy, PINK1 signaling regulates mitochondrial fusion and fission (Van Laar and Berman, 2013). Mitofusin 2 (MFN2) is a GTPase involved in mitochondrial fusion that is phosphorylated by PINK1 and ubiquitinated by Parkin for degradation (Youle and van der Bliek, 2012). Mitochondrial fission factor (MFF) is required for mitochondrial recruitment of Dynamin 1-Like (DNM1L) during fission in mammalian cells (Otera et al., 2010). It has been shown that PINK1 phosphorylates TNF-receptor associated protein 1 (TRAP1) (Pridgeon et al., 2007), that in turn downregulates the expression of fission proteins MFF and DNM1L (Takamura et al., 2012). Therefore a defective PINK1 function may favor fission, although the effect of PINK1 kinase deficiency on fusion/fission dynamics is a matter of controversy (Scarffe et al., 2014). In this study, we first investigated the mitochondrial dynamics and the expression pattern of other PARK genes in fibroblast and differentiated dopamine neurons from patients and asyntomatic carriers from a Spanish kindred (Samaranch et al., 2010) and age-matched controls. This led us to unveil an up-regulation of LRRK2 in the PINK1 mutants and a bidirectional interaction between these two PARK gene products. 5 Azkona et al. 2015 Increased LRRK2 in PINK1 mutants Material and Methods Human samples Skin samples were obtained from four subjects expressing mutated forms of PINK1 diagnosed at the Hospital Universitario Insular de Gran Canaria (La Palma de Gran Canaria, Spain) and from age-matched healthy individuals at the Hospital Donostia and Onkologikoa (San Sebastian, Spain). Subjects with PINK1 gene alterations included two individuals with a c.1488+1G >A mutation (asymptomatic carriers, denoted as PINK1-exon7) and two individuals with an additional deletion c.1252_1488 (affected Parkinson’s disease patients, denoted as PINK1-exon7/del). Demographic data are provided in Supplementary Table 1. The two Parkinson’s disease patients presented an early- onset, typical parkinsonian syndrome, characteristic of PINK1-associated Parkinson’s disease (Samaranch et al., 2010). All subjects gave informed consent for the study using forms approved by the Ethical Committee on the Use of Human Subjects in Research at the Hospital Universitario Insular de Gran Canaria and the Hospital Donostia. Dermal fibroblasts were cultivated in DMEM (High Glucose modification, Sigma Aldrich®) with 10% of fetal calf serum (Invitrogen), 2 mM L-glutamine (Sigma) and 1 % Penicillin/Streptomycin (Sigma), as described previously (Lopez de Maturana et al., 2014). Genetic analysis PINK1 variants were analyzed by conventional PCR using a primer pair designed to amplify a region expanding exons 6 and 8 (Samaranch et al., 2010). Total RNA and cDNA were obtained as detailed below. Cycling conditions were standard. Primer sequences (Samaranch et al., 2010) are provided in Supplementary Table 2. GAPDH was used as the reference gene. 6 Azkona et al. 2015 Increased LRRK2 in PINK1 mutants Standard G-band karyotypes of the iPSC clones used in the study were performed at the Clinical Genetics Unit, Policlinica Gipuzkoa, San Sebastian (Spain). Quantitative RT-PCR Total RNA was extracted using TRIzol® total RNA isolation reagent (Gibco®, Life Technologies) and the RNeasy Qiaprep (Qiagen). cDNA was synthesized from total RNA using random hexamers according to the GeneAmp® RNA PCR Core Kit (Life Technologies) and the High-Capacity cDNA RT kit (Applied Biosystems®). Real- time PCR was performed using SYBR® Green PCR Master Mix (Applied Biosystems®) and the StepOneTM Detection System (Applied Biosystems®). Primer sequences are provided in Supplementary Table 2. Comparative analysis of gene expression levels (∆∆Ct) was carried out using GAPDH as reference. ATP content Cellular ATP was measured using the Luminiscent ATP Detection kit (Abcam). Briefly, cells were harvested with
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