Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on a global scale. One of the main molecular mechanisms responsible for the development of Neuro-PASC, in individuals of all ages, is the formation and inadequate proteolysis/clearance of phase-separated amyloid crystalline aggregates—a hallmark feature of aging-related neurodegenerative disorders. Amyloidogenesis during viral infection and persistence is a natural, inevitable, protective defense response that is exacerbated by SARS-CoV-2. Acting as chemical catalyst, SARS-CoV-2 accelerates hydrophobic collapse and the heterogeneous nucleation of amorphous amyloids into stable β-sheet aggregates. The clearance of amyloid aggregates is most effective during slow wave sleep, when high levels of adenosine triphosphate (ATP)—a biphasic modulator of biomolecular condensates—and melatonin are available to solubilize amyloid aggregates for removal. The dysregulation of mitochondrial dynamics by SARS-CoV-2, in particular fusion and fission homeostasis, impairs the proper formation of distinct mitochondrial subpopulations that can remedy challenges created by the diversion of substrates away from oxidative phosphorylation towards glycolysis to support viral replication and maintenance. The subsequent reduction of ATP and inhibition of melatonin synthesis during slow wave sleep results in incomplete brain clearance of amyloid aggregates, leading to the development of neurological manifestations commonly associated with age-related neurodegenerative disorders. Exogenous melatonin not only prevents mitochondrial dysfunction but also elevates ATP production, effectively augmenting the solubilizing effect of the adenosine moiety to ensure the timely, optimal disaggregation and clearance of pathogenic amyloid aggregates in the prevention and attenuation of Neuro-PASC.