Biology subjects

Worley, P.

Publications and source records attributed to Worley, P..

3 recordsLinked to original sources

bioRxiv2023

An autophagy adaptor TRIAD3A promotes tau fibrillation by phase separation

Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report an RBR-type E3 ligase TRIAD3A functions as a novel autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing ageprogressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyzes a novel mixed K11/K63 polyubiquitin chain and self assembles into liquid-liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and via LC3 interacting regions targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to amyloid aggregates without the transitional liquid phase of tau. In vivo studies reveal TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis, and increases pathological tau spreading. In human Alzheimers disease brain, TRIAD3A colocalizes with tau amyloid in multiple histological forms suggesting a role in tau homeostasis. TRIAD3A is the first autophagic adaptor that utilizes E3-ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Sleep and circadian rhythm disruption by NPTX2 loss of function

Sleep and circadian rhythm disruption (SCRD) is commonly observed in aging, especially in individuals who experience progressive cognitive decline to mild cognitive impairment (MCI) and Alzheimers disease (AD). However, precise molecular mechanisms underlying the association between SCRD and aging are not fully understood. Orexin A is a well-characterized "sleep neuropeptide" that is expressed in hypothalamic neurons and evokes wake behavior. The importance of Orexin is exemplified in narcolepsy where it is profoundly down-regulated. Interestingly, the synaptic immediate early gene NPTX2 is co-expressed in Orexin neurons and is similarly reduced in narcolepsy. NPTX2 is also down-regulated in CSF of some cognitively normal older individuals and predicts the time of transition from normal cognition to MCI. The association between Orexin and NPTX2 is further evinced here where we observe that Orexin A and NPTX2 are highly correlated in CSF of cognitively normal aged individuals and raises the question of whether SCRD that are typically attributed to Orexin A loss of function may be modified by concomitant NPTX2 down-regulation. Is NPTX2 an effector of sleep or simply a reporter of orexin-dependent SCRD? To address this question, we examined NPTX2 KO mice and found they retain Orexin expression in the brain and so provide an opportunity to examine the specific contribution of NPTX2 to SCRD. Our results reveal that NPTX2 KO mice exhibit a disrupted circadian onset time, coupled with increased activity during the sleep phase, suggesting difficulties in maintaining states. Sleep EEG indicates distinct temporal allocation shifts across vigilance states, characterized by reduced wake and increased NREM time. Evident sleep fragmentation manifests through alterations of event occurrences during Wake and NREM, notably during light transition periods, in conjunction with an increased frequency of sleep transitions in NPTX2 KO mice, particularly between Wake and NREM. EEG spectral analysis indicated significant shifts in power across various frequency bands in the wake, NREM, and REM states, suggestive of disrupted neuronal synchronicity. An intriguing observation is the diminished occurrence of sleep spindles, one of the earliest measures of human sleep disruption, in NPTX2 KO mice. These findings highlight the effector role of NPTX2 loss of function as an instigator of SCRD and a potential mediator of sleep disruption in aging.

neuroscience↗

bioRxiv2021

All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected novel form of experience-dependent circuit plasticity. In layer 2/3 of mouse visual cortex monocular deprivation triggers a complete, "all-or-none", elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (PyrPV). This circuit plasticity is unique as it is transient, local and discrete. It lasts only one day, and it does not manifest as widespread changes in synaptic strength, rather, only about half of local connections are lost and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of PyrPV is contingent on a reduction of the protein neuropentraxin2 (NPTX2). Functionally, the loss of PyrPV is absolutely necessary for ODP. We surmise, therefore, that this "all-or-none" loss of local PyrPV circuitry gates experience-dependent cortical plasticity.

neuroscience↗