Abstract
The aggregation of α-synuclein (α-syn) is a major factor behind the onset of Parkinson’s disease (PD). Sublocalization of this protein may be relevant for the formation of multimeric α-syn oligomeric configurations, insoluble aggregates that form Lewy bodies in PD brains. Processing of this protein aggregation is regulated by associations with distinct lipid classes. For instance, instability of lipid raft (LR) microdomains, membrane regions with a particular lipid composition, is an early event in the development of PD. However, the relevance of membrane microdomains in the regulation and trafficking of the distinct α-syn configurations associated with PD remains unexplored. In this study, using 6- and 14-month-old healthy and MPTP-treated animals as a model of PD, we have investigated the putative molecular alterations of raft membrane microstructures, and their impact on α-syn dynamics and conformation. A comparison of lipid analyses of LR microstructures and non-raft (NR) fractions showed alterations in gangliosides, cholesterol, polyunsaturated fatty acids (PUFA) and phospholipids in the midbrain and cortex of aged and MPTP-treated mice. In particular, the increase of PUFA and phosphatidylserine (PS) during aging correlated with α-syn multimeric formation in NR. In these aggregates, α-syn was phosphorylated in pSer129, the most abundant post-transductional modification of α-syn promoting toxic aggregation. Interestingly, similar variations in PUFA and PS content correlating with α-syn insoluble accumulation were also detected in membrane microstructures from the human cortex of incidental Parkinson Disease (iPD) and PD, as compared to healthy controls. Furthermore, structural changes in membrane lipid microenvironments may induce rearrangements in raft-interacting proteins involved in other neuropathologies. Therefore, we also investigated the dynamic of other protein markers involved in cognition and memory impairment such as metabotropic glutamate receptor 5 (mGluR5), ionotropic NMDA receptor (NMDAR2B), prion protein (PrPc) and amyloid precursor protein (APP), whose activity depends on membrane lipid organization. We observed a decline of these protein markers in LR fractions with the progression of aging and pathology. Overall, our findings demonstrate that lipid alterations in membranous compartments promoted by brain aging and PD-like injury may have an effect on α-syn aggregation and segregation in abnormal multimeric structures.
Highlights
Parkinson’s disease (PD) is a condition associated with aging that affects different brain areas, in particular the substantia nigra pars compacta (SNpc)
Aged lipid rafts (LRs) exhibit altered raft lipidomic profiles and physicochemical properties that affect protein associations and may contribute to the cell-cell propagation of toxic α-syn aggregates (Marin et al, 2017; Rodriguez et al, 2018). In this order of ideas, we have demonstrated in the human frontal cortex of both incidental and advanced PD subjects, the presence of lipid changes in LRs that correlate with the progression of the disease (Fabelo et al, 2011; Diaz et al, 2018)
The mouse monoclonal antibodies against synuclein 4D6 clone, anti-amyloid precursor protein (APP), the rabbit polyclonal antibodies against, respectively, pSer129 α-syn, NMDAR2B, Flotillin-1, and the rabbit monoclonal antibody against alpha synuclein [EPR20535], and anti-metabotropic glutamate receptor 5 (mGluR5) were from Abcam (Cambridge, United Kingdom)
Summary
Parkinson’s disease (PD) is a condition associated with aging that affects different brain areas, in particular the substantia nigra pars compacta (SNpc). It is the most prevalent clinical manifestation of a family of neurodegenerative diseases characterized by an abnormal accumulation of aggregates of the protein α-synuclein (α-syn) in neurons, nerve fibers and glial cells, aptly named synucleinopathies (McCann et al, 2014). Most data agree that accumulating α-syn insoluble oligomers is a main neuropathological feature of PD and related synucleinopathies (Rockenstein et al, 2014; Burre et al, 2015; Benskey et al, 2016; Villar-Pique et al, 2016), it is still controversial whether low size protofibrils may cause neuronal death (Breydo et al, 2012; Lashuel et al, 2013). The synaptic localization of α-syn is mediated by binding with high affinity to membrane lipid microenvironments, thereby contributing to the normal functionality of the protein (Fortin et al, 2004; Stockl et al, 2008)
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