Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients
| Autor: | Philippe Lucarelli, Johan Tisserand, Jens Christian Schwamborn, Christian Jaeger, Amy C. Harms, Deborah Gérard, Enrico Glaab, Kathrin Hemmer, Xiaobing Qing, Emanuel Berger, Lasse Sinkkonen, Thomas Hankemeier, Silvia Bolognin, Paul Antony, Sarah Louise Nickels, Jonas Walter, Thomas Sauter, Rashi Halder, Christine Klein, Javier Jarazo |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell Survival Neurology [D14] [Human health sciences] Induced Pluripotent Stem Cells Racemases and Epimerases Context (language use) Biology medicine.disease_cause Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Cell Line 03 medical and health sciences 0302 clinical medicine Neural Stem Cells medicine Genetic predisposition Serine Humans Genetic Predisposition to Disease Cell Self Renewal Induced pluripotent stem cell Genetics Mutation Neurologie [D14] [Sciences de la santé humaine] Parkinson Disease Phenotype LRRK2 Penetrance nervous system diseases 3. Good health 030104 developmental biology Neurology Serine racemase Case-Control Studies Neurology (clinical) Geriatrics and Gerontology 030217 neurology & neurosurgery |
| Zdroj: | Parkinsonism & Related Disorders Parkinsonism & Related Disorders, 67, 48-55. ELSEVIER SCI LTD |
| ISSN: | 1353-8020 |
| DOI: | 10.1016/j.parkreldis.2019.09.018 |
| Popis: | Parkinson's disease (PD) is a multifactorial disorder with complex etiology. The most prevalent PD associated mutation, LRRK2-G2019S is linked to familial and sporadic cases. Based on the multitude of genetic predispositions in PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patients' genetic background act as susceptibility factors for developing PD. To assess LRRK2-G2019S modifiers, we used human induced pluripotent stem cell-derived neuroepithelial stem cells (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal and viability, as well as impaired serine metabolism. In patient cells, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. In this context we identified the gene serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the aberrant phenotypes. Its enzymatic product, n-serine, rescued altered cellular phenotypes. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment. |
| Databáze: | OpenAIRE |
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