Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease

Abstract

Huntington’s disease is characterized by a complex and heterogeneous pathogenic profile. Studies have shown that disturbance in lipid homeostasis may represent a critical determinant in the progression of several neurodegenerative disorders. The recognition of perturbed lipid metabolism is only recently becoming evident in HD. In order to provide more insight into the nature of such a perturbation and into the effect its modulation may have in HD pathology, we investigated the metabolism of Sphingosine-1-phosphate (S1P), one of the most important bioactive lipids, in both animal models and patient samples. Here, we demonstrated that S1P metabolism is significantly disrupted in HD even at early stage of the disease and importantly, we revealed that such a dysfunction represents a common denominator among multiple disease models ranging from cells to humans through mouse models. Interestingly, the in vitro anti-apoptotic and the pro-survival actions seen after modulation of S1P-metabolizing enzymes allows this axis to emerge as a new druggable target and unfolds its promising therapeutic potential for the development of more effective and targeted interventions against this incurable condition.

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

“…We have recently reported that sphingolipid metabolism is aberrant in HD (Di Pardo et al, 2017a ). Here, in order to provide a clearer picture of the deranged sphingolipid homeostasis in the disease, we investigated any potential alteration of the de novo biosynthetic pathway of these lipids.…”

“…Evidence indicates that defective sphingolipid metabolism may likely contribute to different neurodegenerative conditions, including HD (Desplats et al, 2007 ; Maglione et al, 2010 ; Ceccom et al, 2014a , b ; Couttas et al, 2014 , 2016 ; Di Pardo et al, 2016 , 2017a ). We and others have recently demonstrated that alterations in the sphingolipid metabolism occur early in the disease stage and may play, therefore, a critical role in the pathogenesis of HD (Di Pardo et al, 2016 , 2017a ; Skene et al, 2017 ).…”

“…Snap frozen brain tissues were transferred into glass tubes and stored at −80°C until lipid extraction. Lipids were extracted using a modified Bligh and Dyer method as previously described (Basit et al, 2015 ; Di Pardo et al, 2017a ).…”

“…The recognition of deregulated lipid homeostasis is becoming increasingly evident in HD (Puri, 2001 ; Desplats et al, 2007 ; Valenza and Cattaneo, 2011 ; Handley et al, 2016 ). Over the last years, our group and others have extensively contributed to these findings by demonstrating that sphingolipid metabolism is aberrant in multiple preclinical models and in human post-mortem brain tissues from HD patients (Maglione et al, 2010 ; Di Pardo et al, 2016 , 2017a ; Pirhaji et al, 2016 , 2017 ; Skene et al, 2017 ).…”

Bile Acid Signaling in Neurodegenerative and Neurological Disorders

“…Gene therapy using a stereotaxic injection of adeno-associated virus (AAV)rh10 viral constructs for GFP or human CYP46A1 restored CYP46A1 levels in striatal neurons of R6/2 mice and increasing neuronal survival through production of sterols laneosterol and desmosterol, metabolites of CYP46A1 processing, and reestablishment of normal cholesterol levels [ 93 ]. Sphingosine-1-phosphate metabolism in HD patients and two rodent models has shown aberrant signaling of intermediates and metabolizing enzymes, with increased expression of sphingosine-1-phosphate lyase and decreased expression of sphingosine kinase 1/2 in the striatum of post-mortem humans and HD transgenic models, both in early and late stages of the HD rodent model [ 94 ]. Decreasing the bioavailability of sphingosine-1-phosphate could dismantle downstream signaling from G-protein coupled receptors sphingospine-1-phosphate receptors 1–5 [ 95 ] of which S1PR2 has been shown to have expression in neurons [ 62 ].…”