Sphingosine-1-phosphate: distribution, metabolism and role in the regulation of cellular functions

Pepe

Castaldo

et al. 2019

Front. Mol. Neurosci.

Although several agents have been identified to provide therapeutic benefits in Huntington disease (HD), the number of conventionally used treatments remains limited and only symptomatic. Thus, it is plausible that the need to identify new therapeutic targets for the development of alternative and more effective treatments is becoming increasingly urgent. Recently, the sphingosine-1-phosphate (S1P) axis has been reported to be a valid potential novel molecular target for therapy development in HD. Modulation of aberrant metabolism of S1P in HD has been proved to exert neuroprotective action in vitro settings including human HD iPSC-derived neurons. In this study, we investigated whether promoting S1P production by stimulating Sphingosine Kinase 1 (SPHK1) by the selective activator, K6PC-5, may have therapeutic benefit in vivo in R6/2 HD mouse model. Our findings indicate that chronic administration of 0.05 mg/kg K6PC-5 exerted an overall beneficial effect in R6/2 mice. It significantly slowed down the progressive motor deficit associated with disease progression, modulated S1P metabolism, evoked the activation of pro-survival pathways and markedly reduced the toxic mutant huntingtin (mHtt) aggregation. These results suggest that K6PC-5 may represent a future therapeutic option in HD and may potentially counteract the perturbed brain function induced by deregulated S1P pathways.

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stimulation of Sphingosine Kinase 1 (SPHK1) Is Beneficial in a Huntington’s Disease Pre-clinical Model

Pepe

Castaldo

et al. 2019

Front. Mol. Neurosci.

“…S1P metabolism involves a number of different highly specialized enzymes. S1P is normally synthesized by sphingosine kinase-1 and−2 (SPHK1 and 2) and degraded by sphingosine-1-phosphate phosphatase (SGPP) or lyase (SGPL1) (see Figure 1 ) (Le Stunff et al, 2002 ; Morozov et al, 2013 ). SPHK1 activity is mainly associated with cell survival (Le Stunff et al, 2002 ; Morozov et al, 2013 ; Di Pardo et al, 2017a ), while SPHK2 is widely described as being a dual-function protein whose activity may either guarantee the proper occurrence of physiological events like mitochondrial function and homeostasis as well as regulation of gene expression through inhibition of Class I HDACs or result detrimental mainly suppressing cell growth and promoting apoptosis (Maceyka et al, 2005 ; Hait et al, 2009 ; Riccio, 2010 ; Gomez et al, 2011 ; Strub et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders

Maglione

2018

Front. Neurosci.

Neurodegenerative diseases represent a class of fatal brain disorders for which the number of effective therapeutic options remains limited with only symptomatic treatment accessible. Multiple studies show that defects in sphingolipid pathways are shared among different brain disorders including neurodegenerative diseases and may contribute to their complex pathogenesis. In this mini review, we discuss the hypothesis that modulation of sphingolipid metabolism and their related signaling pathways may represent a potential therapeutic approach for those devastating conditions. The plausible “druggability” of sphingolipid pathways is greatly promising and represent a relevant feature that brings real advantage to the development of new therapeutic options for these conditions. Indeed, several molecules that selectively target sphingolipds are already available and many of them currently in clinical trial for human diseases. A deeper understanding of the “sphingolipid scenario” in neurodegenerative disorders would certainly enhance therapeutic perspectives for these conditions, by taking advantage from the already available molecules and by promoting the development of new ones.

“…Similarly, the sphingolipid metabolite sphingosine-1-phosphate (S1P) regulates several molecular events, essential for brain development and neuronal survival [ 85 , 86 ]. S1P is synthesized by sphingosine kinase-1 and 2 (SPHK1 and 2) and degraded by sphingosine-1-phosphate phosphatase (SGPP) or lyase (SGPL1) (see Figure 3 ) [ 87 , 88 ]. SPHK1 is usually associated with cell survival [ 87 , 88 , 89 ], while SPHK2 represents a dual-function enzyme, which may exert both beneficial and toxic effects [ 90 , 91 , 92 , 93 , 94 ].…”

Section: Overlapping Molecular Pathways Of Hypoxic and Chemical Comentioning

confidence: 99%

“…S1P is synthesized by sphingosine kinase-1 and 2 (SPHK1 and 2) and degraded by sphingosine-1-phosphate phosphatase (SGPP) or lyase (SGPL1) (see Figure 3 ) [ 87 , 88 ]. SPHK1 is usually associated with cell survival [ 87 , 88 , 89 ], while SPHK2 represents a dual-function enzyme, which may exert both beneficial and toxic effects [ 90 , 91 , 92 , 93 , 94 ]. SGPP and SGPL1 activities are fundamental for the maintenance of the balance between S1P and other sphingolipid intermediates that may regulate cell proliferation, growth and survival [ 95 ].…”

Section: Overlapping Molecular Pathways Of Hypoxic and Chemical Comentioning

confidence: 99%

A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

Burtscher

Maglione

et al. 2021

IJMS

Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington’s disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington’s disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington’s disease from this knowledge base.