Cooper, J. M. | Search bioRxiv

bioRxiv2020

LRP1 and SORL1 regulate tau internalization and degradation and enhance tau seeding

The identification of the apoE receptor, LRP1, as an endocytic receptor for tau raises several questions about LRP1s role in tauopathies. Is internalized tau, like other LRP1 ligands, delivered to lysosomes for degradation? Does LRP1 internalize pathological tau leading to cytosolic seeding? Do other, related receptors participate in these processes? We confirm that LRP1 rapidly internalizes tau, leading to efficient lysosomal degradation. Employing brain homogenates from human Alzheimer brain, we find that LRP1 also mediates cytosolic tau seeding. We additionally found that another apoE receptor, SORL1, a gene implicated in AD risk, also mediates tau endocytosis, degradation, and release into the cytoplasm of seed competent species. These data suggest a role for these apoE receptors in tau uptake, as well as the competing processes of degradation and release to the cytoplasm. The balance of these processes may be fundamental to spread of neuropathology across the brain in Alzheimer disease.

neuroscience↗

bioRxiv2018

Recurrent loss-of-function mutations reveal costs to OAS1 antiviral activity in primates

Immune responses counteract infections and can also cause collateral damage to hosts. We investigated functional outcomes of variation in the rapidly evolving antiviral double-stranded RNA (dsRNA) sensing factor Oligoadenylate Synthetase 1 (OAS1) in primates as a model for understanding how individual immune pathways evolve to minimize deleterious effects on host fitness. Upon binding of dsRNAs, OAS1 polymerizes ATP into 2'-5' linked oligoadenylate (2-5A), which in turn activates Latent Ribonuclease (RNase L) to kill virus infected cells. OAS1 can undergo auto-activation by host encoded RNAs, raising the question of how it might evolve to mitigate RNase L-mediated cytotoxicity. Using a new yeast-based growth assay, we observed a pattern of frequent loss of 2-5A synthesis by OAS1 from several species. In gorillas, we identified a polymorphism in a conserved substrate binding residue that severely decreases catalytic function. In contrast, lowered 2-5A generation previously associated with variation in humans results from production of unstable OAS1 isoforms. Examination of OAS1 function in monkeys revealed a spectrum of activities, including the complete loss of 2-5A synthesis in tamarins. Frequent loss of catalytic activity in primates suggests that costs associated with OAS1 activation can be so detrimental to host fitness that its pathogen-protective effects are repeatedly forfeited.

genetics↗