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A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis
Article

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

1
Biochemistry and Molecular Biology Laboratory, Department of Health Science, University of Milan, 20142 Milan, Italy
2
“Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, University of Milan, 20142 Milan, Italy
3
Department of Biology, University of Padova, 35121 Padova, Italy
4
Laboratory of Clinical Biochemistry and Mass Spectrometry, Department of Health Sciences, University of Milan, 20142 Milan, Italy
5
Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy
6
Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy
7
IRCCS Neuromed, 86077 Pozzilli, Italy
8
Department of Health Sciences, University of Milan, 20142 Milan, Italy
*
Authors to whom correspondence should be addressed.
The authors contributed equally to this work.
Academic Editor: Antonella Scorziello
Int. J. Mol. Sci. 2021, 22(12), 6469; https://doi.org/10.3390/ijms22126469
Received: 21 May 2021 / Revised: 8 June 2021 / Accepted: 10 June 2021 / Published: 16 June 2021
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases)
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. View Full-Text
Keywords: Parkinson’s disease; α-synuclein; sphingolipids; ceramide; myriocin; autophagy; oxidative stress Parkinson’s disease; α-synuclein; sphingolipids; ceramide; myriocin; autophagy; oxidative stress
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MDPI and ACS Style

Mingione, A.; Pivari, F.; Plotegher, N.; Dei Cas, M.; Zulueta, A.; Bocci, T.; Trinchera, M.; Albi, E.; Maglione, V.; Caretti, A.; Bubacco, L.; Paroni, R.; Bottai, D.; Ghidoni, R.; Signorelli, P. Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease. Int. J. Mol. Sci. 2021, 22, 6469. https://doi.org/10.3390/ijms22126469

AMA Style

Mingione A, Pivari F, Plotegher N, Dei Cas M, Zulueta A, Bocci T, Trinchera M, Albi E, Maglione V, Caretti A, Bubacco L, Paroni R, Bottai D, Ghidoni R, Signorelli P. Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease. International Journal of Molecular Sciences. 2021; 22(12):6469. https://doi.org/10.3390/ijms22126469

Chicago/Turabian Style

Mingione, Alessandra, Francesca Pivari, Nicoletta Plotegher, Michele Dei Cas, Aida Zulueta, Tommaso Bocci, Marco Trinchera, Elisabetta Albi, Vittorio Maglione, Anna Caretti, Luigi Bubacco, Rita Paroni, Daniele Bottai, Riccardo Ghidoni, and Paola Signorelli. 2021. "Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease" International Journal of Molecular Sciences 22, no. 12: 6469. https://doi.org/10.3390/ijms22126469

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