Links between COVID-19, long COVID, and neurodegeneration: The role of glycosphingolipids

Glycosphingolipids (GSLs) play major roles in viral infections by mediating viral entry and egress from cells in lipid rafts; however, GSLs are also important in neurodegenerative diseases. The role of GSLs in acute COVID-19 infection is critical but remains less-studied in the sequelae of long COVID (post-COVID condition); because the same enzymes that regulate GSL metabolism are critical for viral entry and exit, neuromuscular junctions, neurological function, and cellular metabolism, it is important to determine whether long COVID may increase the risk of subsequent neurodegeneration. SARS-CoV-2 infection alters lipid metabolism and oxygen use and can bind to and modify the expression of neurotrophic GSLs such as GM1 ganglioside. GM1 (N-acetylneuraminic acid) is human-specific and probably evolved as a result of a pandemic 3-2.5 million years ago that drove its selection. GM1 functions as a coreceptor with angiotensin-converting enzyme 2 for SARS-CoV-2 while also being a neurotrophin. Viral multiplication takes place in the endoplasmic reticulum/Golgi apparatus, where GSLs are synthesized. This review defines the complex interaction between viruses, GSLs, and neurodegeneration, which provides new perspectives on the interlinked metabolic changes. A European working group has been set up to assess the risks of neurodegeneration with long COVID, based on potential GSL-mediated mechanisms. SIGNIFICANCE STATEMENT: The SARS-CoV-2 pandemic has resulted in a large number of subjects living with long-term consequences (long COVID). Glycosphingolipids and gangliosides are involved in both viral infections and neurodegeneration; hence, it is important to evaluate whether long COVID may increase the risk of neurodegeneration via this route. This study is the result of a European consortium formed to evaluate this possibility.