Abstract
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 SgII+ vesicles. These results show lipid-dependent changes occur with age in neuronal vesicular membrane compartments that accumulate lipid-stabilized aSYN and pTau.
Highlights
Aging is the primary risk factor for a variety of neurodegenerative diseases, including Parkinson’s Disease (PD)[1] and Alzheimer’s Disease (AD)[2]
The current study shows that the abundance of insoluble, high molecular weight (HMW) aSYN+ aggregates in human idiopathic Parkinson’s disease (PD)-substantia nigra (SN) are linearly correlated with loss of GCase function
Utilizing a cohort of idiopathic PD patients (PD) and healthy subjects (HS) for our comparison, several high molecular weight (HMW) species were detected above the ~17 kDa monomer in PD-SN that were largely absent in HS-SN (Fig. 1A,B)
Summary
Aging is the primary risk factor for a variety of neurodegenerative diseases, including Parkinson’s Disease (PD)[1] and Alzheimer’s Disease (AD)[2]. To investigate lipid-membrane interactions that could be relevant to the observed lipid modifications of aSYN and pTau, we immunofluorescently co-labeled said proteins with large, dense-core vesicle marker SgII in tissues of comparably aged mice of the same genotype.
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