Optineurin is a gatekeeper of mitochondrial health and proteostasis in Alzheimer's disease vulnerable neurons
Tsagkogianni, C.; Trivisonno, M.; Willner, J. S.; Garcia-Molinero, C.; Tang, Y.; Mattina, B.; Wang, W.; Roussarie, J.-P.; Rodriguez, P.
Show abstract
Alterations in autophagy-related pathways and in mitochondrial function have long been associated with the pathology of several neurodegenerative disorders, including Alzheimers disease (AD). However, the cascade of events that links these processes and how they contribute to the early degeneration of specific neuronal subpopulations remain to be understood. Here, we use a data-driven approach and identify Optn as a potential regulator of AD pathology that is highly enriched in vulnerable ECII neurons compared to neurons that degenerate later in the disease continuum. We show that Optineurin downregulation triggers early dysregulation of mitochondrial function, followed by alterations in AD-associated processes, including proteostasis, synaptic function, and neuroinflammation. This is accompanied by ECII neuron loss and astrocyte reactivity in EC neuron projecting areas in the hippocampus. Together our results suggest that Optineurin plays a central role in the maintenance of mitochondrial health and bioenergetics in AD vulnerable neurons and that pathological processes that impair this homeostasis may contribute to the early degeneration of vulnerable ECII neurons.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Neither alpha-synuclein-preformed fibrils derived from patients with GBA1 mutations nor the host murine genotype significantly influence seeding efficacy in the mouse olfactory bulb. 96%
- SNCA triplication disrupts proteostasis and extracellular architecture prior to neurodegeneration in human midbrain organoids 96%
- A topographical atlas of alpha-Synuclein dosage and cell-type expression in the mouse brain and periphery 96%
Similar papers in this journal
- Tau phosphorylated at serine 356 is associated with Alzheimer's disease pathology and can be lowered in mouse and human brain tissue using the NUAK inhibitor WZ4003 96%
- Transient receptor potential vanilloid channel 2 contributes to multi-modal endoplasmic reticulum and perinuclear space dilations that can also be observed in prion-infected mice 96%
- Genome-wide association study and functional validation implicates JADE1 in tauopathy 96%
Similar papers in this journal
Similar papers in this journal
- Tau depletion in human neurons mitigates A beta-driven toxicity 97%
- Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer's disease-like pathology in human cerebral organoids 97%
- Alzheimer's genetic risk factor FERMT2 (Kindlin-2) controls axonal growth and synaptic plasticity in an APP-dependent manner. 96%
Similar papers in this journal
- β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity 96%
- SETD7-mediated lysine monomethylation is abundant on non-hyperphosphorylated nuclear Tau 96%
- A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.