The α-Synuclein seeding assay discriminates between LRRK2 p.Gly2019Ser variant carriers with and without Parkinson’s disease
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Background
Reliable biomarkers for Parkinson’s disease (PD) pathology detection are essential for research. The α-synuclein (aSyn) seed amplification assay (SAA) is a validated biomarker for misfolded aSyn.
Objectives
To assess the association between aSyn SAA and LRRK2 -related PD ( LRRK2 -PD) and its link to mitochondrial genetic burden.
Methods
We included N=76 LRRK2 p.Gly2019Ser variant carriers (N=22 affected, N=54 unaffected), N=714 patients with idiopathic PD (iPD), and N=411 controls from Norway. We analyzed cerebrospinal fluid (CSF)-based aSyn SAA in N=10 PD patients and N=30 unaffected LRRK2 p.Gly2019Ser carriers, alongside N=6 controls and N=56 iPD patients. A mitochondrial polygenic score (MGS) was derived from genotyping data, using PPMI as an additional cohort (iPD: N=355, LRRK2 -PD: N=118).
Results
Seeding was observed in 80%of patients with LRRK2 -PD, and in one unaffected variant carrier (AUC=0.97, CI 0.92-1.00). In a meta-analysis across two PD cohorts, higher MGS was associated with increased aSyn seeding (pooled β=0.38, p=0.028).
Conclusions
CSF-based aSyn SAA can discriminate between LRRK2 -PD and unaffected carriers. Our findings support an association with mitochondrial burden and aSyn seeding.
