Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients

Nickels, S.L.; Walter, J.; Bolognin, S.; Gerard, D.; Jaeger, C.; Qing, X.B.; ... ; Schwamborn, J.C. (2019)

Article / Letter to editor

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.

• All authors: Nickels, S.L.; Walter, J.; Bolognin, S.; Gerard, D.; Jaeger, C.; Qing, X.B.; Tisserand, J.; Jarazo, J.; Hemmer, K.; Harms, A.C.; Halder, R.; Lucarelli, P.; Berger, E.; Antony, P.M.A.; Glaab, E.; Hankemeier, T.; Klein, C.; Sauter, T.; Sinkkonen, L.; Schwamborn, J.C.
• Date: 2019-10-01
• Journal: Parkinsonism & Related Disorders
• Volume: 67
• Pages: 48 - 55
• DOI: doi:10.1016/j.parkreldis.2019.09.018