Lysophospholipids: A Potential Drug Candidates for Neurodegenerative Disorders

Abstract

Neurodegenerative diseases (NDs) commonly present misfolded and aggregated proteins. Considerable research has been performed to unearth the molecular processes underpinning this pathological aggregation and develop therapeutic strategies targeting NDs. Fibrillary deposits of α-synuclein (α-Syn), a highly conserved and thermostable protein, are a critical feature in the development of NDs such as Alzheimer's disease (AD), Lewy body disease (LBD), Parkinson's disease (PD), and multiple system atrophy (MSA). Inhibition of α-Syn aggregation can thus serve as a potential approach for therapeutic intervention. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality, gaining the hotspot in pharmaceutical research. Additionally, interest is growing in the use of food-derived bioactive compounds as intervention agents against NDs via functional foods and dietary supplements. According to reports, dietary bioactive phospholipids may have cognition-enhancing and neuroprotective effects, owing to their abilities to influence cognition and mental health in vivo and in vitro. However, the mechanisms by which lipids may prevent the pathological aggregation of α-Syn warrant further clarification. Here, we review evidence for the potential mechanisms underlying this effect, with a particular focus on how porcine liver decomposition product (PLDP)-derived lysophospholipids (LPLs) may inhibit α-Syn aggregation.

Keywords: amyloid; lysophospholipids; neurodegenerative diseases; α-synuclein.

Figure 1

PLDP is a rich source of phospholipids. PLDP extracted lipids (PEL) was extracted from PLDP using the Bligh and Dyer method. This PEL is a rich source of LPLs, including LPC and LPE. LPC and LPE exerted significant protective effects against LPS-induced inflammation and oxidative stress in microglial cells. Various isoforms of PLA2 enzyme hydrolyze PC and PE at the sn-2 position to form LPLs, including LPC and LPE, respectively. α-Syn is bound to LPLs, which are known to be contained in PEL, strongly inhibit α-Syn aggregation.

Figure 2

Schematic illustration of the potential mechanism underlying lysophospholipid (LPL) and α-Synuclein (α-Syn) aggregation. (A) α-Syn is composed of three domains: the N-terminal, NAC, and C-terminal domains. The N-terminus contains a lipid-binding motif. LPLs lack one fatty acid in comparison to diacylglycerol lipids, and they are much more hydrophilic molecules. (B) In aqueous environments, LPLs undergo basic effects, such as the adsorption of the unfolded monomer α-Syn (positive surface charge) upon release from the surface of the cell membrane (negative surface charge). From experimental data, we hypothesize that when α-Syn is bound to LPLs, LPC18:1 and LPE 18:1 (which are known to be contained in PEL) strongly inhibit α-Syn aggregation.