Ceramides in Parkinson's Disease: From Recent Evidence to New Hypotheses

Abstract

Ceramides (Cer) constitute a class of lipids present in the cell membranes where they act as structural components, but they can also work as signaling molecules. Increasing genetic and biochemical evidence supports a link between deregulation of ceramide metabolism in the brain and neurodegeneration. Here, we provide an overview of the genes and cellular pathways that link Cer with Parkinson's disease and discuss how ceramide pathobiology is gaining increasing interest in the understanding of the pathological mechanisms that contribute to the disease and in the clinical and therapeutic side.

Keywords: Gaucher disease; Parkinson’s disease; ceramides; glucocerebrosidase; insulin; lipid rafts; neuroinflammation.

FIGURE 1

(A) Ceramide (Cer) synthesis pathways and their cellular compartmentalization. The SMase pathway takes place at the plasma membrane, where sphingomyelin is hydrolyzed to Cer by smpd3 and reconverted back by sphingomyelin synthase (sms2). The de novo synthesis sits at the endoplasmic reticulum, where Cer is synthesized starting from the condensation of palmitoyl-CoA and serine by serine palmitoyl-CoA acyltransferase (SPT) and then by the action of dihydrosphingosine synthase (CerS) and desaturase. Cer are further processed by sphingomyelin synthase (sms1) and smpd2 or phosphorylated to Cer-1-phopshate by (CerK) at the trans-Golgi network (TGN). Within the endolysosomal route, a number of enzymes, namely SMases (acid SMase, A-SMase), cerebrosidases (acid b-glucosidase, GBA), ceramidases (acid ceramidase, A-CDase), and Cer synthases (glycosyl synthase, GCS), are involved in the recycling of sphingosine. (B) Cer cell signaling. Cer are bioactive lipids upstream several pathways and local or global dysregulation of Cer amount (yellow) can affect cellular biology at multiple levels thus contributing to PD pathogenesis. Cer directly activate PP2A thus inducing cytoskeletal dynamics through ERMs dephosphorylation or regulating PD-linked proteins (LRRK2, a-syn, Tau). Cer inhibit cell survival through PI3K/AKT and induce apoptosis via BAK/BAX. Cer affect also the autophagic flux via Beclin1/Bcl-2 or mTOR. Changes in membrane fluidity, membrane trafficking, lysosomal functionality induced by Cer unbalance possibly interfere with a-syn up-take and degradation. TLR4 receptor modulation by Cer impacts inflammatory response, Cer synthesis itself and the whole body metabolism (pink boxes).