scholarly journals Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison?

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 191
Author(s):  
Rosa Manzoli ◽  
Lorenzo Badenetti ◽  
Michela Rubin ◽  
Enrico Moro
Keyword(s):  
Axon Guidance ◽  
Neural Circuit ◽  
Axonal Guidance ◽  
Lysosomal Storage ◽  
Relevant Research ◽  
Lysosomal Function ◽  
Guidance Cue ◽  
Tight Connection ◽  
And Function ◽  
Storage Disorders

Axonal trajectories and neural circuit activities strongly rely on a complex system of molecular cues that finely orchestrate the patterning of neural commissures. Several of these axon guidance molecules undergo continuous recycling during brain development, according to incompletely understood intracellular mechanisms, that in part rely on endocytic and autophagic cascades. Based on their pivotal role in both pathways, lysosomes are emerging as a key hub in the sophisticated regulation of axonal guidance cue delivery, localization, and function. In this review, we will attempt to collect some of the most relevant research on the tight connection between lysosomal function and axon guidance regulation, providing some proof of concepts that may be helpful to understanding the relation between lysosomal storage disorders and neurodegenerative diseases.

scholarly journals Multiple Functions of Draxin/Netrin-1 Signaling in the Development of Neural Circuits in the Spinal Cord and the Brain

2021 ◽  
Vol 15 ◽  
Author(s):  
Giasuddin Ahmed ◽  
Yohei Shinmyo
Keyword(s):  
Spinal Cord ◽  
Axon Guidance ◽  
Neural Circuits ◽  
Neural Circuit ◽  
Deleted In Colorectal Cancer ◽  
Guidance Cue ◽  
Thalamocortical Projections ◽  
The Central Nervous System ◽  
Circuit Formation ◽  
The Brain

Axon guidance proteins play key roles in the formation of neural circuits during development. We previously identified an axon guidance cue, named draxin, that has no homology with other axon guidance proteins. Draxin is essential for the development of various neural circuits including the spinal cord commissure, corpus callosum, and thalamocortical projections. Draxin has been shown to not only control axon guidance through netrin-1 receptors, deleted in colorectal cancer (Dcc), and neogenin (Neo1) but also modulate netrin-1-mediated axon guidance and fasciculation. In this review, we summarize the multifaceted functions of draxin and netrin-1 signaling in neural circuit formation in the central nervous system. Furthermore, because recent studies suggest that the distributions and functions of axon guidance cues are highly regulated by glycoproteins such as Dystroglycan and Heparan sulfate proteoglycans, we discuss a possible function of glycoproteins in draxin/netrin-1-mediated axon guidance.

scholarly journals RHO-1 and the Rho GEF RHGF-1 interact with UNC-6/Netrin signaling to regulate growth cone protrusion and microtubule organization in C. elegans

2019 ◽  
Author(s):  
Mahekta R. Gujar ◽  
Aubrie M. Stricker ◽  
Erik A. Lundquist
Keyword(s):  
Axon Guidance ◽  
Growth Cone ◽  
Neural Circuit ◽  
Growth Cones ◽  
Negative Regulator ◽  
Microtubule Organization ◽  
C Elegans ◽  
Guidance Cue ◽  
Rho Gef

AbstractUNC-6/Netrin is a conserved axon guidance cue that directs growth cone migrations in the dorsal-ventral axis of C. elegans and in the vertebrate spinal cord. UNC-6/Netrin is expressed in ventral cells, and growth cones migrate ventrally toward or dorsally away from UNC-6/Netrin. Recent studies of growth cone behavior during outgrowth in vivo in C. elegans have led to a polarity/protrusion model in directed growth cone migration away from UNC-6/Netrin. In this model, UNC-6/Netrin first polarizes the growth cone via the UNC-5 receptor, leading to dorsally biased protrusion and F-actin accumulation. UNC-6/Netrin then regulates protrusion based on this polarity. The receptor UNC-40/DCC drives protrusion dorsally, away from the UNC-6/Netrin source, and the UNC-5 receptor inhibits protrusion ventrally, near the UNC-6/Netrin source, resulting in dorsal migration. UNC-5 inhibits protrusion in part by excluding microtubules from the growth cone, which are pro-protrusive. Here we report that the RHO-1/RhoA GTPase and its activator GEF RHGF-1 inhibit growth cone protrusion and MT accumulation in growth cones, similar to UNC-5. However, growth cone polarity of protrusion and F-actin were unaffected by RHO-1 and RHGF-1. Thus, RHO-1 signaling acts specifically as a negative regulator of protrusion and MT accumulation, and not polarity. Genetic interactions suggest that RHO-1 and RHGF-1 act with UNC-5, as well as with a parallel pathway, to regulate protrusion. The cytoskeletal interacting molecule UNC-33/CRMP was required for RHO-1 activity to inhibit MT accumulation, suggesting that UNC-33/CRMP might act downstream of RHO-1. In sum, these studies describe a new role of RHO-1 and RHGF-1 in regulation of growth cone protrusion by UNC-6/Netrin.Author SummaryNeural circuits are formed by precise connections between axons. During axon formation, the growth cone leads the axon to its proper target in a process called axon guidance. Growth cone outgrowth involves asymmetric protrusion driven by extracellular cues that stimulate and inhibit protrusion. How guidance cues regulate growth cone protrusion in neural circuit formation is incompletely understood. This work shows that the signaling molecule RHO-1 acts downstream of the UNC-6/Netrin guidance cue to inhibit growth cone protrusion in part by excluding microtubules from the growth cone, which are structural elements that drive protrusion.

scholarly journals Differential accumulation of storage bodies with aging defines discrete subsets of microglia in the healthy brain

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jeremy Carlos Burns ◽  
Bunny Cotleur ◽  
Dirk M Walther ◽  
Bekim Bajrami ◽  
Stephen J Rubino ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Cell Death ◽  
Molecular Level ◽  
Adult Life ◽  
Lysosomal Storage ◽  
Lysosomal Function ◽  
Transmission Electron ◽  
Related Proteins ◽  
Storage Disorders

To date, microglia subsets in the healthy CNS have not been identified. Utilizing autofluorescence (AF) as a discriminating parameter, we identified two novel microglia subsets in both mice and non-human primates, termed autofluorescence-positive (AF+) and negative (AF−). While their proportion remained constant throughout most adult life, the AF signal linearly and specifically increased in AF+ microglia with age and correlated with a commensurate increase in size and complexity of lysosomal storage bodies, as detected by transmission electron microscopy and LAMP1 levels. Post-depletion repopulation kinetics revealed AF− cells as likely precursors of AF+ microglia. At the molecular level, the proteome of AF+ microglia showed overrepresentation of endolysosomal, autophagic, catabolic, and mTOR-related proteins. Mimicking the effect of advanced aging, genetic disruption of lysosomal function accelerated the accumulation of storage bodies in AF+ cells and led to impaired microglia physiology and cell death, suggestive of a mechanistic convergence between aging and lysosomal storage disorders.

scholarly journals The Role of Exosomes in Lysosomal Storage Disorders

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 576
Author(s):  
Adenrele M. Gleason ◽  
Elizabeth G. Woo ◽  
Cindy McKinney ◽  
Ellen Sidransky
Keyword(s):  
Cell Types ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Lysosomal Disorders ◽  
Lysosomal Dysfunction ◽  
Endosomal Membranes ◽  
A Cell ◽  
The Central Nervous System ◽  
And Function ◽  
Storage Disorders

Exosomes, small membrane-bound organelles formed from endosomal membranes, represent a heterogenous source of biological and pathological biomarkers capturing the metabolic status of a cell. Exosomal cargo, including lipids, proteins, mRNAs, and miRNAs, can either act as inter-cellular messengers or are shuttled for autophagic/lysosomal degradation. Most cell types in the central nervous system (CNS) release exosomes, which serve as long and short distance communicators between neurons, astrocytes, oligodendrocytes, and microglia. Lysosomal storage disorders are diseases characterized by the accumulation of partially or undigested cellular waste. The exosomal content in these diseases is intrinsic to each individual disorder. Emerging research indicates that lysosomal dysfunction enhances exocytosis, and hence, in lysosomal disorders, exosomal secretion may play a role in disease pathogenesis. Furthermore, the unique properties of exosomes and their ability to carry cargo between adjacent cells and organs, and across the blood–brain barrier, make them attractive candidates for use as therapeutic delivery vehicles. Thus, understanding exosomal content and function may have utility in the treatment of specific lysosomal storage disorders. Since lysosomal dysfunction and the deficiency of at least one lysosomal enzyme, glucocerebrosidase, is associated with the development of parkinsonism, the study and use of exosomes may contribute to an improved understanding of Parkinson disease, potentially leading to new therapeutics.

scholarly journals The Class I E3 Ubiquitin Ligase TRIM67 Modulates Brain Development and Behavior

2017 ◽  
Author(s):  
Nicholas P. Boyer ◽  
Caroline Monkiewicz ◽  
Sheryl S. Moy ◽  
Stephanie L. Gupton
Keyword(s):  
Brain Development ◽  
Axon Guidance ◽  
Neuronal Development ◽  
Sensorimotor Gating ◽  
Brain Regions ◽  
Class I ◽  
Guidance Cue ◽  
Evolutionarily Conserved ◽  
And Function ◽  
And Behavior

ABSTRACTSpecific class I members of the TRIM family of E3 ubiquitin ligases have been implicated in neuronal development from invertebrates to mammals. The single invertebrate class I TRIM and mammalian TRIM9 regulate axon branching and guidance in response to the axon guidance cue netrin-1, whereas mammalian TRIM46 establishes the axon initial segment. In humans, mutations in TRIM1 and TRIM18 are implicated in Optiz Syndrome, characterized by midline defects and often mild intellectual disability. TRIM67 is the most evolutionarily conserved vertebrate class I TRIM, yet is the least studied. Here we show that TRIM67 interacts with both its closest paralog TRIM9 and the netrin receptor DCC, and is differentially enriched in specific brain regions at specific developmental points. We describe the anatomical and behavioral consequences of deletion of murine Trim67. While viable, mice lacking Trim67 display severe impairments in spatial memory, cognitive flexibility, social novelty preference, muscle function and sensorimotor gating. Additionally, they exhibit abnormal anatomy of several brain regions, including the hippocampus, striatum and thalamus, as well as the corpus callosum. This study demonstrates the necessity for TRIM67 in appropriate brain development and function.SIGNIFICANCE STATEMENTAs a family, class I TRIM E3 ubiquitin ligases play important roles in neuronal development and function, potentially cooperatively. TRIM67 is the most evolutionarily conserved class I TRIM and is developmentally regulated and brain-enriched. Deletion of murine Trim67 results in malformations of a subset subcortical brain regions and of cortical and subcortical myelinated fiber tracts, as well as deficits in spatial memory, motor function, sociability and sensorimotor gating. We conclude that TRIM67 is critical for appropriate brain development and behavior, potentially downstream of the axon guidance cue netrin, and in cooperation with class I TRIM9.

Lysosomal Storage Disease: Revealing Lysosomal Function and Physiology

Physiology ◽  
2010 ◽  
Vol 25 (2) ◽  
pp. 102-115 ◽  
Author(s):  
Emma J. Parkinson-Lawrence ◽  
Tetyana Shandala ◽  
Mark Prodoehl ◽  
Revecca Plew ◽  
Glenn N. Borlace ◽  
...  
Keyword(s):  
Lysosomal Storage Disorder ◽  
Storage Disease ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Lysosomal Degradation ◽  
Storage Material ◽  
Disease Pathogenesis ◽  
Lysosomal Function ◽  
Vesicular Traffic ◽  
Storage Disorders

The discovery over five decades ago of the lysosome, as a degradative organelle and its dysfunction in lysosomal storage disorder patients, was both insightful and simple in concept. Here, we review some of the history and pathophysiology of lysosomal storage disorders to show how they have impacted on our knowledge of lysosomal biology. Although a significant amount of information has been accrued on the molecular genetics and biochemistry of lysosomal storage disorders, we still do not fully understand the mechanistic link between the storage material and disease pathogenesis. However, the accumulation of undegraded substrate(s) can disrupt other lysosomal degradation processes, vesicular traffic, and lysosomal biogenesis to evoke the diverse pathophysiology that is evident in this complex set of disorders.

scholarly journals Transmembrane Batten disease proteins interact with a shared network of vesicle sorting proteins to regulate synaptic composition and function.

2021 ◽  
Author(s):  
Mitchell J. Rechtzigel ◽  
Brandon L Meyerink ◽  
Hannah Leppert ◽  
Tyler B Johnson ◽  
Jacob T. Cain ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Batten Disease ◽  
Lysosomal Storage ◽  
Associated Proteins ◽  
The Central Nervous System ◽  
And Function ◽  
Shared Network ◽  
Storage Disorders

Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e. SNAREs and tethers) and aberrant synaptic SNARE dynamics in vivo, demonstrating a novel shared etiology.

scholarly journals The ubiquitylome of developing cortical neurons

2020 ◽  
Author(s):  
Shalini Menon ◽  
Dennis Goldfarb ◽  
Emily M. Cousins ◽  
M. Ben Major ◽  
Stephanie L. Gupton
Keyword(s):  
Axon Guidance ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Cortical Neurons ◽  
Spatial Learning And Memory ◽  
Form And Function ◽  
Guidance Cue ◽  
Morphological Responses ◽  
And Function

AbstractTRIM9 and TRIM67 are neuronally-enriched E3 ubiquitin. Both genes are required for neuronal morphological responses to the axon guidance cue netrin-1. For example, our previously published work demonstrated that the actin polymerase VASP and the netrin receptor DCC exhibit TRIM9 dependent ubiquitylation that is lost upon netrin stimulation. Deletion of either gene in the mouse results in subtle neuroanatomical anomalies yet overt deficits in spatial learning and memory. Despite their role in neuronal form and function, the identity of few TRIM9 or TRIM67 substrates are known. Here we performed ubiquitin remnant profiling approach in cultured wildtype and knockout murine embryonic cortical neurons to identify ubiquitylated peptides and proteins, with the ultimate goal of identifying substrates of TRIM9 and TRIM67 that exhibited reduced ubiquitylation in the absence of the ligase. This work reveals the ubiquitylome of developing cortical neurons.

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