Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients.

  • Integrated BioBank of Luxembourg
October 01, 2019 By:
  • Nickels SL
  • Walter J
  • Bolognin S
  • Gerard 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.

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.

2019 Oct. Parkinsonism Relat Disord.67:48-55. Epub 2019 Sep 19.
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