Constitutive KO mouse

Case study

Model for idiopathic Parkinson’s disease (idPD)

‍Zhou Q, Yen A, Rymarczyk G, Asai H, Trengrove C, Aziz N, Kirber MT, Mostoslavsky G, Ikezu T, Wolozin B, Bolotina VM.
Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease.
Nat Commun. 2016.

Cells from idPD patients reveal a significant deficiency in store-operated PLA2G6-dependent Ca2+ signaling. The Pla2g6 gene (PARK14 disease locus) is poorly understood.

Model: Mice that constitutively lack the Pla2g6 gene mimicking the pathology observed in idPD patients.

Aim: Explore the origins of human age-dependent PD from the new perspective of PARK14 and the store-operated Ca2+ signaling, opening new opportunities for finding a cure for idPD.

Results: The molecular impairment of PLA2G6-dependent Ca2+ signaling triggers a sequence of pathological events of autophagic dysfunction, progressive loss of dopaminergic (DA) neurons in substantia nigra pars compacta and age-dependent L-DOPA-sensitive motor dysfunction.

Figure 1. PLA2G6 KO mice mimic store-operated Ca2+ entry (SOCE) deficiency in idPD patients.

A) Live primary skin fibroblasts from idPD and control donors were pretreated with thapsigargin (TG) to induce Ca2+ influx prior to Ca2+ addition. On average, there was more than 40% reduction in TG-induced Ca2+ influx in idPD patients compared with the control group.

‍B-C) MEFs (B) and iPSC-derived DA neurons (C) from WT and PLA2G6 KO mice were pretreated with TG prior to CA2+ addition. Impairment of TG-induced Ca2+ influx in the PLA2G6 KO mice mimics the defect found in fibroblasts of idPD patients.

Figure 2. PLA2G6 KO mice develop age-dependent PD-like phenotype.

Progressive motor dysfunction in aging KO, but not in WT mice developed at an age range that aligns with that typical of idPD in humans. Human age equivalent is shown below.