Biology subjects

Kauwe, G.

Publications and source records attributed to Kauwe, G..

3 recordsLinked to original sources

bioRxiv2023

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimers disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase M{zeta} (PKM{zeta}) to maintain synaptic plasticity and memory despite tau mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

neuroscience↗

bioRxiv2022

A retrograde GCN2/eIF2α, but ATF4 independent, mechanism maintains synaptic strength under acute amino acid scarcity at the NMJ

Neuronal response to nutrient availability plays an important role in the maintenance of cellular homeostasis and behavioral response to the environment in higher eukaryotes. However, we know little about how neuronal function is influenced by acute changes in nutrients at high resolution. Taking advantage of powerful fly genetics and the amenability of the Drosophila larval neuromuscular junction (NMJ), we have investigated the synaptic response to acute amino acid restriction. Our findings indicate that the presence of general control nonderepressible 2 (GCN2) and phosphorylation of its target eukaryotic initiation factor 2 alpha (eIF2) are essential for the ability of the NMJ to maintain normal neurotransmitter output when the larvae are deprived of amino acids. Surprisingly, activating transcription factor 4 (ATF4), which normally acts downstream of GCN2/eIF2, appears dispensable in this regulation. Furthermore, we show that GCN2/eIF2 dependent cascade acts retrogradely from muscle back to motoneuron to adjust synaptic release. These results provide a mechanistic insight into the intricate regulation of synaptic strength through the action of GCN2 when organisms are faced with amino acid scarcity.

neuroscience↗

bioRxiv2021

Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease

Tau (MAPT) drives neuronal dysfunction in Alzheimers disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established activity-dependent interactions of Tau with presynaptic vesicle proteins during Tau secretion and mapped the exact APEX-tau-induced biotinylated tyrosines to the cytosolic domains of the interacting vesicular proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Taus interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multi-modal and dynamic Tau interactomes with unprecedented spatiotemporal resolution shed novel insights into Taus role in neuronal function and disease-related processes with potential therapeutic targets to block Tau-mediated pathogenesis.

neuroscience↗