Jason Newton

Sphingolipid metabolism has emerged as a regulatory interface between lipid homeostasis, organelle stress, and genome maintenance. Although sphingolipids are essential structural components of cellular membranes, specific metabolites also function as bioactive mediators that shape cellular responses to genotoxic stress. In this review, we examine how canonical and atypical sphingolipid pathways influence the DNA damage response through three mechanistic axes. First, ceramide-centered stress signaling links radiation, chemotherapy, and inflammatory injury to kinase and phosphatase pathways, mitochondrial apoptosis, and checkpoint-associated cell-fate decisions. Second, nuclear sphingolipid metabolism, particularly sphingosine kinase 2-dependent production of sphingosine-1-phosphate, regulates chromatin-associated transcriptional programs through modulation of histone deacetylase activity. Third, persistent sphingolipid imbalance promotes metabolic stress by disrupting lysosomal turnover, mitochondrial function, endoplasmic reticulum homeostasis, and redox balance, thereby increasing endogenous oxidative DNA damage. We also discuss atypical sphingolipids, including 1-deoxysphingolipids generated through altered serine palmitoyltransferase substrate utilization, as emerging mediators of mitochondrial dysfunction and genome instability. Finally, we consider the relevance of these mechanisms to cancer, lysosomal storage disorders, and neurodegenerative diseases, where sphingolipid dysregulation may influence therapeutic responses and disease progression. Together, these position sphingolipid metabolism as an integrated regulatory network connecting cellular stress signaling, chromatin regulation, organelle dysfunction, and genome stability.

Sphingolipid metabolism has emerged as a regulatory interface between lipid homeostasis, organelle stress, and genome maintenance. Although sphingolipids are essential structural components of cellular membranes, specific metabolites also function as bioactive mediators that shape cellular responses to genotoxic stress. In this review, we examine how canonical and atypical sphingolipid pathways influence the DNA damage response through three mechanistic axes. First, ceramide-centered stress signaling links radiation, chemotherapy, and inflammatory injury to kinase and phosphatase pathways, mitochondrial apoptosis, and checkpoint-associated cell-fate decisions. Second, nuclear sphingolipid metabolism, particularly sphingosine kinase 2-dependent production of sphingosine-1-phosphate, regulates chromatin-associated transcriptional programs through modulation of histone deacetylase activity. Third, persistent sphingolipid imbalance promotes metabolic stress by disrupting lysosomal turnover, mitochondrial function, endoplasmic reticulum homeostasis, and redox balance, thereby increasing endogenous oxidative DNA damage. We also discuss atypical sphingolipids, including 1-deoxysphingolipids generated through altered serine palmitoyltransferase substrate utilization, as emerging mediators of mitochondrial dysfunction and genome instability. Finally, we consider the relevance of these mechanisms to cancer, lysosomal storage disorders, and neurodegenerative diseases, where sphingolipid dysregulation may influence therapeutic responses and disease progression. Together, these findings position sphingolipid metabolism as an integrated regulatory network connecting cellular stress signaling, chromatin regulation, organelle dysfunction, and genome stability.

Sphingolipids, first discovered in 1874 by Johann Thudicum, are among the eight recognized classes of lipids and are present in essentially all plants, animals, and fungi, as well as some viruses and prokaryotes. In mammals, sphingolipids are enriched in the central nervous system (CNS), where they play vital roles in tissue development; membrane structure; cell adhesion and recognition; and, importantly, signaling. A subset of sphingolipids including ceramide, glucosylceramide, and sphingosine has been shown to have bioactive properties, but two sphingolipids in particular (ceramide-1-phosphate and sphingosine-1-phosphate) have been shown to exert their effects at least in part due to the activation of cell surface-expressed G protein-coupled receptors. In the CNS, sphingosine-1-phosphate signaling has specifically emerged as a productive therapeutic target for the treatment of neurodegenerative disease, with the first small molecule targeting sphingosine-1-phosphate receptors approved roughly 15 years ago for the treatment of multiple sclerosis. As more specific activators and inhibitors of these receptors have been developed and entered the clinical trial pipeline, now is an appropriate time to examine the current state of our knowledge of the role that these receptors play in the CNS and highlight the current landscape of available modulators targeting these pathways.

JOURNAL/nrgr/04.03/01300535-202606000-00068/figure1/v/2026-04-16T195327Z/r/image-tiff Alzheimer’s disease is initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated Alzheimer’s disease with lysosomal storage and metabolic disorders, and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions. However, the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined. Here, we applied a disease similarity approach to identify unknown molecular targets of Alzheimer’s disease by using transcriptomic data from congenital diseases known to increase Alzheimer’s disease risk, namely Down syndrome, Niemann-Pick type C disease, and mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of Alzheimer’s disease pathology, many of which have never been associated with Alzheimer’s disease. We then investigated common molecular alterations in brain samples from a Niemann-Pick type C disease mouse model by juxtaposing them with brain samples of both human and mouse models of Alzheimer’s disease. Detailed phenotypic, molecular, chronological, and biological aging analyses revealed that the Npc1 ^{tm(I1061T)Dso} mouse model can serve as a potential short-lived in vivo model for brain aging and Alzheimer’s disease research. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on Alzheimer’s disease research while highlighting shortcomings and lack of correlation in diverse in vitro models. Considering the lack of an Alzheimer’s disease mouse model that recapitulates the physiological hallmarks of brain aging, the short-lived Npc1 ^{tm(I1061T)Dso} mouse model can further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of Alzheimer’s disease from a perspective of accelerated brain aging.

Sphingolipids, first discovered in the 1874 by Johann Thudicum, are one of the 8 recognized classes of lipids and are present in essentially all plants, animals, and fungi as well as some viruses and prokaryotes. In mammals’ sphingolipids are enriched in the central nervous system (CNS) where they play vital roles in tissue development, membrane structure, cell adhesion and recognition, and importantly signaling. A subset of sphingolipids has been shown to have bioactive properties including ceramide, glucosylceramide, and sphingosine but two sphingolipids in particular (ceramide-1-phosphate and sphingosine-1-phosphate) have been shown to exert their effects at least in part due to activation of cell surface expressed G protein-coupled receptors. In the CNS sphingosine-1-phosphate signaling in particular has emerged as a productive therapeutic target for the treatment of neurodegenerative disease, with the first small molecule targeting sphingosine-1-phosphate receptors approved roughly 15 years ago for the treatment of multiple sclerosis. As more specific activators and inhibitors of these receptors have been developed and entered the clinical trial pipeline it is an appropriate time to examine the current state of our knowledge of the role that these receptors play in the CNS and highlight the current landscape of available modulators targeting these pathways.

Since its first description in 1906 by Dr. Alois Alzheimer, Alzheimer’s disease (AD) has been the most common type of dementia. Initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated AD with lysosomal storage and metabolic disorders, and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions. However, the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined. Here, we applied a disease similarity approach to identify unknown molecular targets of AD by using transcriptomic data from congenital diseases known to increase AD risk, namely Down Syndrome, Niemann Pick Disease Type C (NPC), and Mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of AD pathology, many of which have never been associated with AD. We then investigated common molecular alterations in brain samples from an NPC disease mouse model by juxtaposing them with brain samples of both human and mouse models of AD. Detailed phenotypic and molecular analyses revealed that the NPC ^mut mouse model can serve as a potential short-lived in vivo model for AD research and for understanding molecular factors affecting brain aging. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on AD research while highlighting shortcomings and lack of correlation in diverse in vitro models. Considering the lack of an AD mouse model that recapitulates the physiological hallmarks of brain aging, the characterization of a short-lived NPC mouse model will further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of AD from a perspective of accelerated brain aging.