Ceramide contributes to pathogenesis and may be targeted for therapy in VCP inclusion body myopathy

Abstract

Background/Objective Knock-in homozygote VCPR155H/R155H mutant mice are a lethal model of Valosin Containing Protein (VCP)-associated Inclusion Body Myopathy, Paget disease of bone, frontotemporal dementia, and amyotropic lateral sclerosis. Ceramide (d18:1/16:0) levels are elevated in skeletal muscle of the mutant mice, compared to wild-type controls. Moreover, exposure to a lipid-enriched diet reverses lethality, improves myopathy and normalizes ceramide levels in these mutant mice, suggesting that dysfunctions in lipid-derived signaling are critical to disease pathogenesis. Here, we investigated the potential role of ceramide in VCP disease using pharmacological agents that manipulate the ceramide levels in myoblast cultures from VCP mutant mice and VCP patients. Methods Myoblasts from wild-type, VCPR155H/+ and VCPR155H/R155H mice, as well as patient induced pluripotent stem cells (iPSCs), were treated with an inhibitor of ceramide degradation to increase ceramide via acid ceramidase (ARN082) for proof of principle. Three chemically distinct inhibitors of ceramide biosynthesis via serine palmitoyl-CoA transferase (L-cycloserine, myriocin or ARN14494) used as a therapeutic strategy to reduce ceramide in myoblasts. Results Acid ceramidase inhibitor, ARN082, elevated cellular ceramide levels and concomitantly enhanced pathology. Conversely inhibitors of ceramide biosynthesis L-cycloserine, myriocin and ARN14494 reduced ceramide production. The results point to ceramide-mediated signaling as a key contributor to pathogenesis in VCP disease, and suggests that manipulating this pathway by blocking ceramide biosynthesis might exert beneficial effects in patients with this condition. Conclusion The ceramide pathway appears to be critical in VCP pathogenesis, and small-molecule inhibitors of ceramide biosynthesis might provide therapeutic benefit in VCP and, related neurodegenerative diseases.

Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging

“…Hence, the preservation of the function of these pathways may have contributed to the improved health span in aged mice and increased life span in worms treated with myriocin. This is consistent with previous reports showing that ceramides are key signaling contributors to the pathogenesis of various proteotoxic neuromuscular diseases such as Parkinson's disease, progressive cerebello-cerebral atrophy type 2, Huntington's disease, spinal muscular atrophy, and valosin-containing protein (VCP)-associated inclusion body myopathy (43,(48)(49)(50). Given the known effects of ceramides on human pathophysiology, such as in insulin resistance, dyslipidemia, and cardiovascular diseases (19)(20)(21)(22), it will be of interest to study whether ceramide dysregulation also causes proteotoxicity in these obesity-fueled disorders.…”

The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition

“…A recent report found that motor neurons from ALS patients with p97 mutations exhibited more contacts between the ER and mitochondria relative to controls 60 . Furthermore, several studies suggest that a lipid-controlled diet or modulation of lipid biosynthesis may have therapeutic implications in mouse models of p97 proteinopathies 61 , 62 . Thus, altered organelles contacts and downstream lipid synthesis warrants further investigation in p97 associated diseases.…”

The Cure VCP Scientific Conference 2021: Molecular and clinical insights into neurodegeneration and myopathy linked to multisystem proteinopathy-1 (MSP-1)

“…In collaboration with Dr. Daniele Piomelli (University of California, Irvine), they found they could inhibit ceramide biosynthesis by targeting serine palmitoyltransferase (SPT) to effectively reduce ceramide levels in mouse and human primary myoblasts. This inhibition reduced various markers of disease including reducing cytoplasmic TDP-43, autophagy markers, LC3B and p62, and ubiquitin ( Weiss et al, 2021 ). It should be noted that mutations in SPT are linked to hereditary sensory neuropathy type 1.…”