Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease; it is characterized by the loss of dopaminergic neurons in the midbrain and the accumulation of neuronal inclusions, mainly consisting of α-synuclein (α-syn) fibrils in the affected regions. The prion-like property of the pathological forms of α-syn transmitted via neuronal circuits has been considered inherent in the nature of PD. Thus, one of the potential targets in terms of PD prevention is the suppression of α-syn conversion from the functional form to pathological forms. Recent studies suggested that α-syn interacts with synaptic vesicle membranes and modulate the synaptic functions. A series of studies suggest that transient interaction of α-syn as multimers with synaptic vesicle membranes composed of phospholipids and other lipids is required for its physiological function, while an α-syn-lipid interaction imbalance is believed to cause α-syn aggregation and the resultant pathological α-syn conversion. Altered lipid metabolisms have also been implicated in the modulation of PD pathogenesis. This review focuses on the current literature reporting the role of lipids, especially phospholipids, and lipid metabolism in α-syn dynamics and aggregation processes.
Highlights
Several neurodegenerative diseases, including Parkinson’s disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are described as synucleinopathies, which are characterized by the progressive accumulation of fibrillized α-synuclein (α-syn) in the affected regions [1,2]
This review focuses on the literature linking α-syn function mainly with phospholipids, which is a major constituent molecule of biomembranes and membrane structures, as well as how these interactions participate in the physiological function and the pathogenesis in PD
Some studies have shown that a monomer form of α-syn changes into pathogenic β-sheet-rich small fibrils, subsequeAnltplyheal-osynngautcilnegininhtaostawhisitgehddaemgyreloeiodffisbeqriulse,nacnedhfionmaolllyogfoyrmwiinthgaLpBosli[p3o];ptrhoistepinros,cweshs iacphpfeuanrcstion to diinsrulipptidthteravnesspicourtlaarstrsatrnuscptourrtaal ncodmorpgoanneenlltes foufnlciptioopnrsootef itnhepamrittioclcehso, nendzriyam, eantdicocpolfaascmtoicrsr,eatincdulluigmands (ER)f,oarncdellly-ssuorsfoamceerse, ceevpetnotrusa[l4ly6]l.eAadminpghitpoantheiucrhoenlaicledse, afitrhst[3fo].und in the amino acid sequences of plasma apolipoprotein, are a secondary structural motif involved in lipid membrane association
Summary
Several neurodegenerative diseases, including Parkinson’s disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are described as synucleinopathies, which are characterized by the progressive accumulation of fibrillized α-synuclein (α-syn) in the affected regions [1,2]. A variety of lipids exist in the brain, including fatty acids, triacylglycerols, phospholipids, sterols, and glycolipids These lipid species are utilized for energy metabolism, protein modification, signal mediators, and biomembrane and organelle functions. The findings of PLA2G6, VPS13C, LIMP2, GBA1, and GALC as the genes responsible for or genetic risks of PD with prominent LB deposition strengthen the concept that lipids are involved in the aggregation and propagation of α-syn [23,24,25,26,27]. These genes are suggested to regulate metabolism, transport, and degradation of lipids [24,25,27,28,29]. We would like to discuss potential therapeutic targets for lipid modification in PD
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