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.

Inhibition of ceramide synthesis reduces α‐synuclein proteinopathy in a cellular model of parkinson’s disease

Trinchera M.;Paroni R.;
2021-01-01

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.
2021
Autophagy; Ceramide; Myriocin; Oxidative stress; Parkinson’s disease; Sphingolipids; α‐synuclein; Animals; Biosynthetic Pathways; Cell Line, Tumor; Ceramides; Disease Management; Disease Susceptibility; Fatty Acids, Monounsaturated; Humans; Intracellular Space; Oxidative Stress; Parkinson Disease; Sphingolipids; alpha-Synuclein
Mingione, A.; Pivari, F.; Plotegher, N.; Cas, M. D.; Zulueta, A.; Bocci, T.; Trinchera, M.; Albi, E.; Maglione, V.; Caretti, A.; Bubacco, L.; Paroni, R.; Bottai, D.; Ghidoni, R.; Signorelli, P.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2115349
 Attenzione

L'Ateneo sottopone a validazione solo i file PDF allegati

Citazioni
  • ???jsp.display-item.citation.pmc??? 12
  • Scopus 17
  • ???jsp.display-item.citation.isi??? 15
social impact