Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-33474-z
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Funding
- NIH/NINDS [1R01NS092667]
- NIH/NIA [R01AG060195]
- Consolidated Anti-Aging Foundation
- Orchard Foundation
- Harold and Ronna Cooper Post-Doctoral Fellowship for Parkinson's Disease Research
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS092667] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG060195] Funding Source: NIH RePORTER
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This report demonstrates insoluble alpha-synuclein (aSYN)+ aggregates in human sporadic Parkinson's disease (PD) midbrain that are linearly correlated with loss of glucocerebrosidase (GCase) activity. To identify early protein-lipid interactions that coincide with loss of lipid homeostasis, an aging study was carried out in mice with age-dependent reductions in GCase function. The analysis identified aberrant lipid-association by aSYN and hyperphosphorylated Tau (pTau) in a specific subset of neurotransmitter-containing, Secretogranin II (SgII)+ large, dense-core vesicles (LDCVs) responsible for neurotransmission of dopamine and other monoamines. The lipid vesicle-accumulation was concurrent with loss of PSD-95 suggesting synaptic destabilization. aSYN overexpression in the absence of lipid deregulation did not recapitulate the abnormal association with Sg II+ vesicles. These results show lipid-dependent changes occur with age in neuronal vesicular membrane compartments that accumulate lipid-stabilized aSYN and pTau.
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