Liquid-Liquid Phase Separation in Physiology and Pathophysiology of the Nervous System

Molecules within cells are segregated into functional domains to form various organelles. While some of those organelles are delimited by lipid membranes demarcating their constituents, others lack a membrane enclosure. Recently, liquid-liquid phase separation (LLPS) revolutionized our view of how segregation of macromolecules can produce membraneless organelles. While the concept of LLPS has been well studied in the areas of soft matter physics and polymer chemistry, its significance has only recently been recognized in the field of biology. It occurs typically between macromolecules that have multivalent interactions. Interestingly, these features are present in many molecules that exert key functions within neurons. In this review, we cover recent topics of LLPS in different contexts of neuronal physiology and pathology

A central role for dityrosine crosslinking of Amyloid-β in Alzheimer’s disease

Background Alzheimer’s disease (AD) is characterized by the deposition of insoluble amyloid plaques in the neuropil composed of highly stable, self-assembled Amyloid-beta (Aβ) fibrils. Copper has been implicated to play a role in Alzheimer’s disease. Dimers of Aβ have been isolated from AD brain and have been shown to be neurotoxic. Results We have investigated the formation of dityrosine cross-links in Aβ42 formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress with elevated copper and shown that dityrosine can be formed in vitro in Aβ oligomers and fibrils and that these links further stabilize the fibrils. Dityrosine crosslinking was present in internalized Aβ in cell cultures treated with oligomeric Aβ42 using a specific antibody for dityrosine by immunogold labeling transmission electron microscopy. Results also revealed the prevalence of dityrosine crosslinks in amyloid plaques in brain tissue and in cerebrospinal fluid from AD patients. Conclusions Aβ dimers may be stabilized by dityrosine crosslinking. These results indicate that dityrosine cross-links may play an important role in the pathogenesis of Alzheimer’s disease and can be generated by reactive oxygen species catalyzed by Cu2+ ions. The observation of increased Aβ and dityrosine in CSF from AD patients suggests that this could be used as a potential biomarker of oxidative stress in AD