AUTHOR=Galatolo Daniele , Rocchiccioli Silvia , Di Giorgi Nicoletta , Dal Canto Flavio , Signore Giovanni , Morani Federica , Ceccherini Elisa , Doccini Stefano , Santorelli Filippo Maria 

TITLE=Proteomics and lipidomic analysis reveal dysregulated pathways associated with loss of sacsin

JOURNAL=Frontiers in Neuroscience

VOLUME=18

YEAR=2024

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1375299

DOI=10.3389/fnins.2024.1375299

ISSN=1662-453X

ABSTRACT=<sec><title>Introduction</title><p>Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare incurable neurodegenerative disease caused by mutations in the <italic>SACS</italic> gene, which codes for sacsin, a large protein involved in protein homeostasis, mitochondrial function, cytoskeletal dynamics, autophagy, cell adhesion and vesicle trafficking. However, the pathogenic mechanisms underlying sacsin dysfunction are still largely uncharacterized, and so attempts to develop therapies are still in the early stages.</p></sec><sec><title>Methods</title><p>To achieve further understanding of how processes are altered by loss of sacsin, we used untargeted proteomics to compare protein profiles in ARSACS fibroblasts versus controls.</p></sec><sec><title>Results</title><p>Our analyses confirmed the involvement of known biological pathways and also implicated calcium and lipid homeostasis in ARSACS skin fibroblasts, a finding further verified in SH-SY5Y <italic>SACS</italic><sup>–/–</sup> cells. Validation through mass spectrometry-based analysis and comparative quantification of lipids by LC-MS in fibroblasts revealed increased levels of ceramides coupled with a reduction of diacylglycerols.</p></sec><sec><title>Discussion</title><p>In addition to confirming aberrant Ca<sup>2+</sup> homeostasis in ARSACS, this study described abnormal lipid levels associated with loss of sacsin.</p></sec>