Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients

Nickels SL, Walter J, Bolognin S, Gérard D, Jaeger C, Qing X, Tisserand J, Jarazo J, Hemmer K, Harms A, Halder R, Lucarelli P, Berger E, Antony PMA, Glaab E, Hankemeier T, Klein C, Sauter T, Sinkkonen L, Schwamborn JC.

Parkinsonism and Related Disorders, Volume 67, pages 48–55, September 2019. https://doi.org/10.1016/j.parkreldis.2019.09.018

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.

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