De novo Synthesis of Sphingolipids Is Defective in Experimental Models of Huntington's Disease

Abstract

Alterations of lipid metabolism have been frequently associated with Huntington's disease (HD) over the past years. HD is the most common neurodegenerative disorder, with a complex pathogenic profile, typically characterized by progressive striatal and cortical degeneration and associated motor, cognitive and behavioral disturbances. Previous findings from our group support the idea that disturbed sphingolipid metabolism could represent an additional hallmark of the disease. Although such a defect represents a common biological denominator among multiple disease models ranging from cells to humans through mouse models, more efforts are needed to clearly define its clinical significance and the role it may play in the progression of the disease. In this study, we provided the first evidence of a defective de novo biosynthetic pathway of sphingolipids in multiple HD pre-clinical models. qPCR analysis revealed perturbed gene expression of sphingolipid-metabolizing enzymes in both early and late stage of the disease. In particular, reduction in the levels of sptlc1 and cerS1 mRNA in the brain tissues from manifest HD mice resulted in a significant decrease in the content of dihydroSphingosine, dihydroSphingosine-1-phospahte and dihydroCeramide [C18:0] as assessed by mass spectrometry. Moreover, in vitro studies highlighted the relevant role that aberrant sphingolipid metabolism may have in the HD cellular homeostasis. With this study, we consolidate the evidence of disturbed sphingolipid metabolism in HD and demonstrate for the first time that the de novo biosynthesis pathway is also significantly affected in the disease. This finding further supports the hypothesis that perturbed sphingolipid metabolism may represent a crucial factor accounting for the high susceptibility to disease in HD.

Sphingolipid composition of circulating extracellular vesicles after myocardial ischemia

“…Sphingolipids are one of the major lipid constituents of eukaryotic cells and, beside their structural role, they also function as signaling molecules for maintenance of cell membrane integrity, apoptosis, cellular damage or oxidative stress response, cell growth, senescence and migration, endothelial cell function, and inflammatory signaling 13 , 33 – 35 . Thus, profiling of circulating sphingolipids in patients may offer relevant information and allow identification of specific disorders and disrupted metabolic pathways 35 . Such diagnostic approach can be further implemented by recent technological advances in mass spectrometry (MS), which allows precise characterization of different lipid molecules 2 .…”

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy

“…The importance of sphingolipids in neurodegenerative disease has recently expanded beyond lysosomal disorders or classical sphingolipidosis. Secondary disturbances of these lipid species including DhCer have been shown in Huntington disease (17) and Alzheimer's patients (18).…”

Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders

“…Expression of S1P-metabolizing enzymes was reported to be aberrant in multiple HD settings (Di Pardo et al, 2017a , b ; Pirhaji et al, 2017 ). Levels of SPHK1 was found reduced in brain tissues form two fully manifest HD mouse models (R6/2 and YAC128 mice), and most importantly, in brain tissues from HD patients (Di Pardo et al, 2017a ).…”

“…Ultimately, synthesis of de novo sphingolipids is also affected in HD animals, even at early stage of the disease (Di Pardo et al, 2017b ). This alteration determines a robust reduction of certain dihydroceramide species along with dihydrosphingosine and dihydroS1P (Di Pardo et al, 2017b ).…”