Crockett, M. | bioRxiv Science

bioRxiv2024

Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation

Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimers disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles are selectively removed from the mitochondrial network. The precise mechanism through which this occurs remains unclear. Previously, we showed that tau which has been mutated at Thr-231 to glutamic acid to mimic an Alzheimers-relevant phospho-epitope expressed early in disease selectively inhibits oxidative stress-induced mitophagy in C. elegans. Here, we use immortalized mouse hippocampal neuronal cell lines to extend that result into mammalian cells. Specifically, we show that phosphomimetic tau at Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly inhibits mitophagy induction by paraquat, a potent inducer of mitochondrial oxidative stress. Moreover, a combination of immunologic and biochemical approaches demonstrates that the levels of the mitophagy receptor FKBP8, significantly decrease in response to paraquat in cells expressing EC or EM tau mutants, but not in cells expressing wildtype tau. In contrast, paraquat treatment results in a decrease in the levels of the mitophagy receptors FUNDC1 and BNIP3 in the presence of both wildtype tau and the tau mutants. Interestingly, FKBP8 is normally trafficked to the endoplasmic reticulum during oxidative stress induced mitophagy, and our results support a model where this trafficking is impacted by disease-relevant tau, perhaps through a direct interaction. We provide new insights into the molecular mechanisms underlying tau pathology in Alzheimers disease and highlight FKBP8 receptor as a potential target for mitigating mitochondrial dysfunction in neurodegenerative diseases.

neuroscience↗

bioRxiv2019

Neural signatures of model-free learning when avoiding harm to self and other

Moral behaviour requires learning how our actions help or harm others. Theoretical accounts of learning propose a key division between model-free algorithms that efficiently cache outcome values in actions and model-based algorithms that prospectively map actions to outcomes, a distinction that may be critical for moral learning. Here, we tested the engagement of these learning mechanisms and their neural basis as participants learned to avoid painful electric shocks for themselves and a stranger. We found that model-free learning was prioritized when avoiding harm to others compared to oneself. Model-free prediction errors for others relative to self were tracked in the thalamus/caudate at the time of the outcome. At the time of choice, a signature of model-free moral learning was associated with responses in subgenual anterior cingulate cortex (sgACC), and resisting this model-free influence was predicted by stronger connectivity between sgACC and dorsolateral prefrontal cortex. Finally, multiple behavioural and neural correlates of model-free moral learning varied with individual differences in moral judgment. Our findings suggest moral learning favours efficiency over flexibility and is underpinned by specific neural mechanisms.

neuroscience↗