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- Title
Neuronopathic GBA1L444P Mutation Accelerates Glucosylsphingosine Levels and Formation of Hippocampal Alpha-Synuclein Inclusions.
- Authors
Mahoney-Crane, Casey L.; Viswanathan, Megha; Russell, Dreson; Curtiss, Rachel A. C.; Freire, Jennifer; Bobba, Sai Sumedha; Coyle, Sean D.; Kandebo, Monika; Lihang Yao; Bang-Lin Wan; Hatcher, Nathan G.; Smith, Sean M.; Marcus, Jacob N.; Volpicelli-Daley, Laura A.
- Abstract
The most common genetic risk factor for Parkinson's disease (PD) is heterozygous mutations GBA1, which encodes for the lysosomal enzyme, glucocerebrosidase. Reduced glucocerebrosidase activity associates with an accumulation of abnormal a-synuclein (a-syn) called Lewy pathology, which characterizes PD. PD patients heterozygous for the neuronotypic GBA1L444P mutation (GBA11/L444P) have a 5.6-fold increased risk of cognitive impairments. In this study, we used GBA11/L444P mice of either sex to determine its effects on lipid metabolism, expression of synaptic proteins, behavior, and a-syn inclusion formation. At 3 months of age, GBA11/L444P mice demonstrated impaired contextual fear conditioning, and increased motor activity. Hippocampal levels of vGLUT1 were selectively reduced in GBA11/L444P mice. We show, using mass spectrometry, that GBA1L444P expression increased levels of glucosylsphingosine, but not glucosylceramide, in the brains and serum of GBA11/L444P mice. Templated induction of a-syn pathology in mice showed an increase in a-syn inclusion formation in the hippocampus of GBA11/L444P mice compared with GBA11/1 mice, but not in the cortex, or substantia nigra pars compacta. Pathologic a-syn reduced SNc dopamine neurons by 50% in both GBA11/1 and GBA11/L444P mice. Treatment with a GlcCer synthase inhibitor did not affect abundance of a-syn inclusions in the hippocampus or rescue dopamine neuron loss. Overall, these data suggest the importance of evaluating the contribution of elevated glucosylsphingosine to PD phenotypes. Further, our data suggest that expression of neuronotypic GBA1L444P may cause defects in the hippocampus, which may be a mechanism by which cognitive decline is more prevalent in individuals with GBA1-PD.
- Subjects
ALPHA-synuclein; DOPAMINERGIC neurons; PARKINSON'S disease; HIPPOCAMPUS (Brain); SUBSTANTIA nigra; THETA rhythm; GLUCOSE-6-phosphate dehydrogenase deficiency
- Publication
Journal of Neuroscience, 2023, Vol 43, Issue 3, p501
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0680-22.2022