Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients. (October 2019)

• Record Type: Journal Article
• Authors: Nickels, Sarah Louise; Walter, Jonas; Bolognin, Silvia; Gérard, Deborah; Jaeger, Christian; Qing, Xiaobing; Tisserand, Johan; Jarazo, Javier; Hemmer, Kathrin; Harms, Amy; Halder, Rashi; Lucarelli, Philippe; Berger, Emanuel; Antony, Paul M.A.; Glaab, Enrico; Hankemeier, Thomas; Klein, Christine; Sauter, Thomas; Sinkkonen, Lasse; Schwamborn, Jens Christian
• Is Part Of: Parkinsonism & related disorders. Volume 67(2019)
• Page Start: 48
• Page End: 55
• Publication Date: 2019-10
• Subjects: Parkinson's disease -- LRRK2-G2019S -- Neuroepithelial stem cells -- Genetic background -- Susceptibility factor -- Serine racemase -- Second hit; Parkinson's disease -- Periodicals; Movement disorders -- Periodicals; Movement Disorders -- Periodicals; Nerve Degeneration -- Periodicals; Nervous System Diseases -- Periodicals; Parkinson Disease -- Periodicals; Tremor -- Periodicals; Parkinson, Maladie de -- Périodiques; Parkinson's disease; 616.833
• DOI: 10.1016/j.parkreldis.2019.09.018
• Languages: English
• ISSNs: 1353-8020

Abstract

Abstract: 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, d -serine, rescued altered cellular phenotypes. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment. Highlights: Stem cells from LRRK2-G2019S patients show impaired self-renewal, viability, and serine metabolism. Patient phenotypes only partly depend on LRRK2-G2019S, the PD genetic background contributes. Identification of SRR as a possible susceptibility factor within the PD genetic background. The enzymatic product of SRR, D-serine rescues background related phenotypes within PD patient cells.