Glycolipids in Parkinson's disease: beyond neuronal function

Abstract

Glycolipid balance is key to normal body function, and its alteration can lead to a variety of diseases involving multiple organs and tissues. Glycolipid disturbances are also involved in Parkinson's disease (PD) pathogenesis and aging. Increasing evidence suggests that glycolipids affect cellular functions beyond the brain, including the peripheral immune system, intestinal barrier, and immunity. Hence, the interplay between aging, genetic predisposition, and environmental exposures could initiate systemic and local glycolipid changes that lead to inflammatory reactions and neuronal dysfunction. In this review, we discuss recent advances in the link between glycolipid metabolism and immune function and how these metabolic changes can exacerbate immunological contributions to neurodegenerative diseases, with a focus on PD. Further understanding of the cellular and molecular mechanisms that control glycolipid pathways and their impact on both peripheral tissues and the brain will help unravel how glycolipids shape immune and nervous system communication and the development of novel drugs to prevent PD and promote healthy aging.

Keywords: Parkinson's; central nervous system; glycolipids; immune system; inflammation; intestine.

Fig. 1

Role of GL in non‐neuronal cell types. GL changes in microglia, astrocytes, BBB, T cells, and in the intestine are associated with altered tissue function. GLs exert both proinflammatory and anti‐inflammatory properties by affecting glial cell activation, cytokine release, proliferation, and cellular migration. GL modulates T‐cell function and antigen presentation. BBB permeability and extravasation are affected by GL changes. Lastly, GLs are key to intestinal function and GL metabolic changes can lead to disruption of the gut barrier and altered microbiota composition. Such pathways could contribute to PD pathogenesis. aGalCer, α‐galactosylceramide; BFT, Bacteroides fragilis toxin; bSMase, bacterial sphingomyelinase; DCF1, dendritic cell factor 1; GCase, glucocerebrosidase; GlcCer, glucosylceramide; GPNMB, glycoprotein nonmetastatic melanoma protein B; IBA1, ionized calcium‐binding adaptor molecule 1; LacCer, lactosylceramide; NOS, nitric oxide species; nsGLs, neolacto‐series glycolipids; ROS, reactive oxygen species; S1P, sphingosine 1‐phosphate; S1PR, sphingosine 1‐phosphate receptor; SPLs, sphingolipids; TJP1, tight‐junction protein 1; TLR4, toll‐like receptor 4; UGCG, UDP‐glucose ceramide glucosyltransferase. Created with BioRender.com.