Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a proteinopathy associated with the aggregation of α-synuclein and the formation of lipid–protein cellular inclusions, named Lewy bodies (LBs). LB formation results in impaired neurotransmitter release and uptake, which involve membrane traffic and require lipid synthesis and metabolism. Lipids, particularly ceramides, are accumulated in postmortem PD brains and altered in the plasma of PD patients. Autophagy is impaired in PD, reducing the ability of neurons to clear protein aggregates, thus worsening stress conditions and inducing neuronal death. The inhibition of ceramide synthesis by myriocin (Myr) in SH-SY5Y neuronal cells treated with preformed α-synuclein fibrils reduced intracellular aggregates, favoring their sequestration into lysosomes. This was associated with TFEB activation, increased expression of TFEB and LAMP2, and the cytosolic accumulation of LC3II, indicating that Myr promotes autophagy. Myr significantly reduces the fibril-related production of inflammatory mediators and lipid peroxidation and activates NRF2, which is downregulated in PD. Finally, Myr enhances the expression of genes that control neurotransmitter transport (SNARE complex, VMAT2, and DAT), whose progressive deficiency occurs in PD neurodegeneration. The present study suggests that counteracting the accumulation of inflammatory lipids could represent a possible therapeutic strategy for PD.

Reduced sphingolipid biosynthesis modulates proteostasis networks to enhance longevity

“…In addition, Myr was first identified in a search for antibiotics [13] and anti-inflammatory drugs [14]. More recently, it has shown beneficial effects in treating age-associated diseases including diabetes, cancers, neurological and cardiovascular disorders [15][16][17][18][19][20] and other diseases including muscular dystrophies, cystic fibrosis and retinopathy [21][22][23] Sphingolipids serve as both structural components of cellular membranes and as signal or regulatory molecules influencing many physiological processes, particularly in mammals [15,[24][25][26]. Because most de novo lipid biosynthesis begins in the endoplasmic reticulum and continues in the Golgi Apparatus before the terminal products are distributed to cellular membranes, Myr treatment has the potential to diminish or enhance a variety of processes.…”

“…In addition, Myr was first identified in a search for antibiotics (Kluepfel, Bagli, Baker, Charest, & Kudelski, 1972) and anti-inflammatory drugs (Fujita et al, 1994). More recently, it has shown beneficial effects in treating age-associated diseases including diabetes, cancers, neurological and cardiovascular disorders (Lin, Wang, Marcogliese, & Bellen, 2019; Petit et al, 2020; Piano et al, 2020; Quinville, Deschenes, Ryckman, & Walia, 2021; Tippetts, Holland, & Summers, 2021; Woo et al, 2019) and other diseases including muscular dystrophies, cystic fibrosis and retinopathy (Laurila et al, 2022; Mingione et al, 2021; Shiwani et al, 2021)…”

2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

“…It was used to adjust the signal intensity thresholding and distinguish the region of interest (ROI). Then fluorescence co-localization (Mander’s correlation coefficient, MCC) was determined by evaluating fields acquired blindly in each group and by applying the same selection strategy [ 48 , 49 , 50 ]. The MCC obtained in each group was compared with the control group.…”

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy

“…The inhibition of Cer synthesis through myriocin in SH-SY5Y cells uploaded with α-synuclein promoted the degradation of protein aggregates, triggering autophagy [ 145 ]. Similarly, myriocin improved the outcome and the survival of mice models of motor neuron degeneration [ 146 ], further demonstrating that the modulation of sphingolipid metabolism could be effective in the treatment of neurodegeneration.…”