scholarly journals Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Hui Ye ◽  
Shamsideen A Ojelade ◽  
David Li-Kroeger ◽  
Zhongyuan Zuo ◽  
Liping Wang ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Protein Complex ◽  
Adult Brain ◽  
Aging Brain ◽  
Gtpase Activating Protein ◽  
Ultrastructural Evidence ◽  
Aging Adults ◽  
And Function ◽  
Brain Homeostasis

Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson’s and Alzheimer’s disease, our understanding of retromer function in the adult brain remains limited, in part because Vps35 and Vps26 are essential for development. In Drosophila, we find that Vps29 is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, in Vps29 mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further, Vps29 phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5. With aging, retromer insufficiency triggers progressive endolysosomal dysfunction, with ultrastructural evidence of impaired substrate clearance and lysosomal stress. Our results reveal the role of Vps29 in retromer localization and function, highlighting requirements for brain homeostasis in aging.

scholarly journals Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain

2019 ◽  
Author(s):  
Hui Ye ◽  
Shamsideen Ojelade ◽  
David Li-Kroeger ◽  
Zhongyuan Zuo ◽  
Liping Wang ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Adult Brain ◽  
Aging Brain ◽  
Gtpase Activating Protein ◽  
Ultrastructural Evidence ◽  
Age Dependent ◽  
Aging Adults ◽  
And Function ◽  
Brain Homeostasis

AbstractRetromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson’s and Alzheimer’s disease, our understanding of retromer function in the adult brain remains limited, in part because Vps35 and Vps26 are essential for development. In Drosophila, we find that Vps29 is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, in Vps29 mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further, Vps29 phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5. With aging, retromer insufficiency triggers progressive endolysosomal dysfunction, with ultrastructural evidence of impaired substrate clearance and lysosomal stress. Our results reveal the role of Vps29 in retromer localization and function, highlighting requirements for brain homeostasis in aging.Impact StatementVps29 promotes retromer localization in the adult Drosophila brain, engaging Rab7 and TBC1D5, and its loss triggers age-dependent neuronal impairments in endolysosomal trafficking and synaptic transmission.

scholarly journals P-glycoprotein (ABCB1) and Oxidative Stress: Focus on Alzheimer’s Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Giulia Sita ◽  
Patrizia Hrelia ◽  
Andrea Tarozzi ◽  
Fabiana Morroni
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Drug ◽  
Amyloid A ◽  
P Glycoprotein ◽  
And Function ◽  
The Brain ◽  
Brain Homeostasis

ATP-binding cassette (ABC) transporters, in particular P-glycoprotein (encoded by ABCB1), are important and selective elements of the blood-brain barrier (BBB), and they actively contribute to brain homeostasis. Changes in ABCB1 expression and/or function at the BBB may not only alter the expression and function of other molecules at the BBB but also affect brain environment. Over the last decade, a number of reports have shown that ABCB1 actively mediates the transport of beta amyloid (Aβ) peptide. This finding has opened up an entirely new line of research in the field of Alzheimer’s disease (AD). Indeed, despite intense research efforts, AD remains an unsolved pathology and effective therapies are still unavailable. Here, we review the crucial role of ABCB1 in the Aβtransport and how oxidative stress may interfere with this process. A detailed understanding of ABCB1 regulation can provide the basis for improved neuroprotection in AD and also enhanced therapeutic drug delivery to the brain.

scholarly journals Altered Glutamate Receptor Ionotropic Delta Subunit 2 Expression in Stau2-Deficient Cerebellar Purkinje Cells in the Adult Brain

2019 ◽  
Vol 20 (7) ◽  
pp. 1797 ◽  
Author(s):  
Helena F. Pernice ◽  
Rico Schieweck ◽  
Mehrnoosh Jafari ◽  
Tobias Straub ◽  
Martin Bilban ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Glutamate Receptor ◽  
Rna Binding ◽  
Wheel Running ◽  
Adult Brain ◽  
Learning Abilities ◽  
Cerebellar Purkinje Cells ◽  
And Function ◽  
Delta Subunit

Staufen2 (Stau2) is an RNA-binding protein that is involved in dendritic spine morphogenesis and function. Several studies have recently investigated the role of Stau2 in the regulation of its neuronal target mRNAs, with particular focus on the hippocampus. Here, we provide evidence for Stau2 expression and function in cerebellar Purkinje cells. We show that Stau2 downregulation (Stau2GT) led to an increase of glutamate receptor ionotropic delta subunit 2 (GluD2) in Purkinje cells when animals performed physical activity by voluntary wheel running compared with the age-matched wildtype (WT) mice (C57Bl/6J). Furthermore, Stau2GT mice showed lower performance in motor coordination assays but enhanced motor learning abilities than did WT mice, concomitantly with an increase in dendritic GluD2 expression. Together, our results suggest the novel role of Stau2 in Purkinje cell synaptogenesis in the mouse cerebellum.

scholarly journals GDNF and protection of adult central catecholaminergic neurons

2011 ◽  
Vol 46 (3) ◽  
pp. R83-R92 ◽  
Author(s):  
Alberto Pascual ◽  
María Hidalgo-Figueroa ◽  
Raquel Gómez-Díaz ◽  
José López-Barneo
Keyword(s):  
Current Knowledge ◽  
Physiological Role ◽  
Adult Brain ◽  
Peripheral Neurons ◽  
Central Neurons ◽  
Small Proteins ◽  
Therapeutic Tools ◽  
And Function ◽  
Catecholaminergic Cells

Neurotrophic factors are small proteins necessary for neuron survival and maintenance of phenotype. They are considered as promising therapeutic tools for neurodegenerative diseases. The glial cell line-derived neurotrophic factor (GDNF) protects catecholaminergic cells from toxic insults; thus, its potential therapeutic applicability in Parkinson's disease has been intensely investigated. In recent years, there have been major advances in the analysis of GDNF signaling pathways in peripheral neurons and embryonic dopamine mesencephalic cells. However, the actual physiological role of GDNF in maintaining catecholaminergic central neurons during adulthood is only starting to be unraveled, and the mechanisms whereby GDNF protects central brain neurons are poorly known. In this study, we review the current knowledge of GDNF expression, signaling, and function in adult brain, with special emphasis on the genetic animal models with deficiency in the GDNF-dependent pathways.

Environment and Brain Plasticity: Towards an Endogenous Pharmacotherapy

2014 ◽  
Vol 94 (1) ◽  
pp. 189-234 ◽  
Author(s):  
Alessandro Sale ◽  
Nicoletta Berardi ◽  
Lamberto Maffei
Keyword(s):  
Environmental Enrichment ◽  
Molecular Mechanisms ◽  
Brain Plasticity ◽  
System Development ◽  
Basic Research ◽  
Nervous System Development ◽  
Adult Brain ◽  
Aging Brain ◽  
Cerebral Neurons ◽  
And Function

Brain plasticity refers to the remarkable property of cerebral neurons to change their structure and function in response to experience, a fundamental theoretical theme in the field of basic research and a major focus for neural rehabilitation following brain disease. While much of the early work on this topic was based on deprivation approaches relying on sensory experience reduction procedures, major advances have been recently obtained using the conceptually opposite paradigm of environmental enrichment, whereby an enhanced stimulation is provided at multiple cognitive, sensory, social, and motor levels. In this survey, we aim to review past and recent work concerning the influence exerted by the environment on brain plasticity processes, with special emphasis on the underlying cellular and molecular mechanisms and starting from experimental work on animal models to move to highly relevant work performed in humans. We will initiate introducing the concept of brain plasticity and describing classic paradigmatic examples to illustrate how changes at the level of neuronal properties can ultimately affect and direct key perceptual and behavioral outputs. Then, we describe the remarkable effects elicited by early stressful conditions, maternal care, and preweaning enrichment on central nervous system development, with a separate section focusing on neurodevelopmental disorders. A specific section is dedicated to the striking ability of environmental enrichment and physical exercise to empower adult brain plasticity. Finally, we analyze in the last section the ever-increasing available knowledge on the effects elicited by enriched living conditions on physiological and pathological aging brain processes.

scholarly journals FORMATION AND FUNCTION OF A COMPLEX OF THE C3 PROACTIVATOR WITH A PROTEIN FROM COBRA VENOM

1973 ◽  
Vol 137 (2) ◽  
pp. 451-460 ◽  
Author(s):  
Neil R. Cooper
Keyword(s):  
Protein Complex ◽  
Normal Serum ◽  
Cobra Venom ◽  
Free Solution ◽  
And Function ◽  
Modes Of Interaction

The role of C3 proactivator (C3PA) and a factor isolated from cobra venom (CoF) in the formation of a principle able to cleave C3 was investigated. The results clearly demonstrate two modes of interaction of C3PA with CoF. In isolated form, C3PA and CoF were found to form a reversible protein-protein complex in free solution. This complex had some C3 cleaving activity. In the presence of minute amounts of a partially purified normal serum substance, factor D, the C3PA-CoF complex was stabilized and its efficiency in cleaving C3 was greatly increased. Factor D is thus an activator of C3PA. A firm complex composed of C3PA and CoF, and possessing C3 cleaving activity, was also formed by addition of CoF to serum.

scholarly journals tRNA-Dependent Import of a Transit Sequence-Less Aminoacyl-tRNA Synthetase (LeuRS2) into the Mitochondria of Arabidopsis

2021 ◽  
Vol 22 (8) ◽  
pp. 3808
Author(s):  
Steffen Reinbothe ◽  
Claudia Rossig ◽  
John Gray ◽  
Sachin Rustgi ◽  
Diter von Wettstein ◽  
...  
Keyword(s):  
Protein Complex ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mitochondrial Protein ◽  
Protein Translation ◽  
Trna Synthetase ◽  
In Planta ◽  
Trna Synthetases ◽  
And Function

Aminoacyl-tRNA synthetases (AaRS) charge tRNAs with amino acids for protein translation. In plants, cytoplasmic, mitochondrial, and chloroplast AaRS exist that are all coded for by nuclear genes and must be imported from the cytosol. In addition, only a few of the mitochondrial tRNAs needed for translation are encoded in mitochondrial DNA. Despite considerable progress made over the last few years, still little is known how the bulk of cytosolic AaRS and respective tRNAs are transported into mitochondria. Here, we report the identification of a protein complex that ties AaRS and tRNA import into the mitochondria of Arabidopsis thaliana. Using leucyl-tRNA synthetase 2 (LeuRS2) as a model for a mitochondrial signal peptide (MSP)-less precursor, a ≈30 kDa protein was identified that interacts with LeuRS2 during import. The protein identified is identical with a previously characterized mitochondrial protein designated HP30-2 (encoded by At3g49560) that contains a sterile alpha motif (SAM) similar to that found in RNA binding proteins. HP30-2 is part of a larger protein complex that contains with TIM22, TIM8, TIM9 and TIM10 four previously identified components of the translocase for MSP-less precursors. Lack of HP30-2 perturbed mitochondrial biogenesis and function and caused seedling lethality during greening, suggesting an essential role of HP30-2 in planta.

scholarly journals The Cell-Autonomous Role of Excitatory Synaptic Transmission in the Regulation of Neuronal Structure and Function

Neuron ◽  
2013 ◽  
Vol 78 (3) ◽  
pp. 433-439 ◽  
Author(s):  
Wei Lu ◽  
Eric A. Bushong ◽  
Tiffany P. Shih ◽  
Mark H. Ellisman ◽  
Roger A. Nicoll
Keyword(s):  
Synaptic Transmission ◽  
Structure And Function ◽  
Excitatory Synaptic Transmission ◽  
Neuronal Structure ◽  
And Function

scholarly journals Profiles and Dynamics of the Transcriptome of Microglial Cells Reveal their Inflammatory Status

2021 ◽  
Author(s):  
Keren Zohar ◽  
Elyad Lezmi ◽  
Fanny Reichert ◽  
Tsiona Eliyahu ◽  
Shlomo Rotshenker ◽  
...  
Keyword(s):  
Cell System ◽  
Aging Brain ◽  
Primary Role ◽  
Transient Wave ◽  
Inflammatory Status ◽  
Activated State ◽  
Transcriptional Changes ◽  
Brain Homeostasis

The primary role of microglia in the maintenance of brain homeostasis is to respond to disturbances in the microenvironment. In this study, we cultured murine neonatal microglia and activated them with lipopolysaccharide (LPS) and benzoyl ATP (bzATP) to characterize changes in the transcriptome in response to various in vivo stimuli caused by pathogens, injury, or toxins. Activation by bzATP, an agonist of purinergic receptors, induces a transient wave of transcriptional changes. However, a long-lasting transcriptional profile affecting thousands of genes occurs only following a combination of bzATP and LPS. This profile is dominated by a coordinated induction of cytokines (e.g., IL1-alpha; and IL1-beta), chemokines, and their direct regulators. Many of these inflammatory-related genes are up-regulated by several orders of magnitude. We identified the TNF-alpha and NF-kB pathways as the principal hubs for signaling of interleukin and chemokine induction in this cell system. We propose that primary microglia under controlled activation paradigms can be used for testing reagents that could attenuate their activated state. Such a microglial system could serve as a model for changes occurring in the aging brain and neurodegenerative diseases.

Scanning electron microscopic study of collagen fibrillogenesis and extracellular compartmentalization in the chick embryo tendon

1986 ◽  
Vol 44 ◽  
pp. 208-209
Author(s):  
Grace C.H. Yang
Keyword(s):  
Chick Embryo ◽  
Extracellular Space ◽  
Fibroblast Cell ◽  
Collagen Fibrils ◽  
Electron Microscopic ◽  
Voltage Electron ◽  
Scanning Electron Microscopic Study ◽  
Microscopic Studies ◽  
And Function

The size and organization of collagen fibrils in the extracellular matrix is an important determinant of tissue structure and function. The synthesis and deposition of collagen involves multiple steps which begin within the cell and continue in the extracellular space. High-voltage electron microscopic studies of the chick embryo cornea and tendon suggested that the extracellular space is compartmentalized by the fibroblasts for the regulation of collagen fibril, bundle, and tissue specific macroaggregate formation. The purpose of this study is to gather direct evidence regarding the association of the fibroblast cell surface with newly formed collagen fibrils, and to define the role of the fibroblast in the control and the precise positioning of collagen fibrils, bundles, and macroaggregates during chick tendon development.

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