Objective: To make Parkinson’s disease (PD) mice model and investigate the mechanism how glucocerebrosidase (gba) heterozygous mutations contribute to asyn pathology and development of PD.

Background: The precise pathomechanism of PD remains unclear, and the appropriate animal model is not available yet. Based on genetic findings from PD patients with asyn multiplication and GWAS in PD, we previously generated human asyn Bacterial Artificial Chromosome (BAC) transgenic (snca tg +/+) mice, but they did not show DA neurodegeneration. Recently, heterozygous mutations in gba gene were reported to be a strong risk factor for PD, but its precise in vivo mechanism remains unclear.

Methods: In the present study, we crossed snca tg +/+ mice with gba heterozygous knockout (gba +/-) mice to make PD mice model and investigated the mechanism how gba heterozygous mutations contribute to asyn pathology and development of PD.

Results: These double mutant (dm) mice express human asyn in a physiological manner by its native promoter. Although behavioral test did not detect motor phenotype of PD, the number of tyrosine hydroxylase (TH) positive cells in substantia nigra pars compacta (SNpc) was significantly decreased, and phosphorylated pathological asyn was accumulated in the early or vulnerable regions in PD. Analysis of lipid metabolism associated with GBA revealed that abnormal lipid accumulation only in dm mice. Moreover, the mild overexpression of asyn solely decreased GBA enzymatic activity in snca tg +/+ mice, and dm mice had tendency to have further decreased level of GBA enzymatic activity. Based on these results asyn accumulation and decreased GBA activity, even if gba is in heterozygous status, might make vicious bidirectional loop in vivo and contribute to PD pathology. Also, dm mice showed a defect in assembly of mitochondrial complex 1 protein, presumably contributing to mild DA cell loss in SNpc.

Conclusions: Dm mice of snca tg +/+ mice crossed with gba +/- mice can be mice model for premotor PD with DA neurodegeneration and pathological asyn accumulation. In addition, considering that the decreased GBA activity was reported in idiopathic PD brains and shown to be enhanced by increased asyn expression, to augment the GBA activity or decrease the level of asyn expression is a reasonable strategy for the treatment of PD with or without GBA mutations.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/gba-haploinsufficiency-accelerated-alpha-synuclein-pathology-with-altered-lipid-metabolism-in-a-premotor-model-of-parkinsons-disease/