axonal protein
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Author(s):  
Arthur English

Despite the intrinsically greater capacity for axons to regenerate in injured peripheral nerves than after injury to the central nervous system, functional recovery after most nerve injuries is very poor. A need for novel treatments that will enhance axon regeneration and improve recovery is substantial. Several such experimental treatments have been studied, each based on part of the stereotypical cellular responses that follow a nerve injury. Genetic manipulations of Schwann cells that have transformed from a myelinating to a repair phenotype that either increase their production of axon growth-promoting molecules, decrease production of inhibitors, or both result in enhanced regeneration. Local or systemic application of these molecules or small molecule mimetics of them also will promote regeneration. The success of treatments that stimulate axonal protein synthesis at the site of the nerve injury and in the growing axons, an early and important response to axon injury, is significant, as is that of manipulations of the types of immune cells that migrate into the injury site or peripheral ganglia. Modifications of the extracellular matrix through which the regenerating axons course, including the stimulation of new blood vessel formation, promotes the navigation of nascent regenerating neurites past the injury site, resulting in greater axon regeneration. Experimental induction of expression of regeneration associated gene activity in the cell bodies of the injured neurons is especially useful when regenerating axons must regenerate over long distances to reinnervate targets. The consistently most effective experimental approach to improving axon regeneration in peripheral nerves has been to increase the activity of the injured neurons, either through electrical, optical, or chemogenetic stimulation or through exercise. These activity-dependent experimental therapies show greatest promise for translation to use in patients.


Author(s):  
Priyanka Patel ◽  
Pabitra K. Sahoo ◽  
Amar N. Kar ◽  
Jeffery L. Twiss

Axons can extend long distances from the neuronal cell body, and mRNA translation in axons is used to locally generate new proteins in these distal reaches of the neuron’s cytoplasm. Work over the past two decades has shown that axonal mRNA translation occurs in many different organisms and different neuronal systems. The field has progressed substantially over this time, moving from documenting mRNA translation in axons to understanding how axonal mRNA translation is regulated and what the protein products do for the neuron. Translational regulation in axons extends beyond merely controlling activity of the protein synthesis machinery. Transport of mRNAs into axons, stability of the mRNAs within the axons, and sequestration of mRNAs away from the translational machinery each contribute to determining what proteins are generated in axons, as well as when and where those proteins are generated within the axon. It is now known that thousands of different mRNAs can localize into axons. Based on unique responses to different axonal translation regulating stimuli and events, there clearly is specificity for when different mRNA populations are translated. How that specificity is driven is just now beginning to be understood, and studies emerging over the last five years point to multiple mechanisms for imparting specificity for regulation of axonal protein synthesis responses.


2020 ◽  
Author(s):  
M. Bell ◽  
S. Bachmann ◽  
J. Klimek ◽  
F. Langerscheidt ◽  
H. Zempel

AbstractSomatodendritic missorting of the axonal protein TAU is a hallmark of Alzheimer’s disease and related tauopathies. Cultured rodent primary neurons and iPSC-derived neurons are used for studying mechanisms of neuronal polarity, including TAU trafficking. However, these models are expensive, time-consuming and/or require the sacrification of animals. In this study, we evaluated four differentiation procedures to generate mature neuron cultures from human SH-SY5Y neuroblastoma cells, in comparison to mouse primary neurons, and tested their TAU sorting capacity. We show that SH-SY5Y-derived neurons, differentiated with sequential RA/BDNF treatment, are suitable for investigating axonal TAU sorting. These human neurons show pronounced neuronal polarity, axodendritic outgrowth, expression of the neuronal maturation markers TAU and MAP2, and, importantly, efficient axonal sorting of endogenous and transfected human wild type TAU, similar to primary neurons. We demonstrate that axonal TAU enrichment requires the presence of the C-terminal half, as a C-terminus-lacking construct (N-term-TAUHA) is not axonally enriched in both neuronal cell models. Moreover, SH-SY5Y-derived neurons do not show formation of a classical axon initial segment (AIS), indicated by the lack of Ankyrin G (ANKG) and tripartite motif-containing protein 46 (TRIM46) at the proximal axon, which suggests that successful axonal TAU sorting is independent of classical AIS formation. Taken together, our results suggest i) that SH-SY5Y-derived neurons are a valuable human neuronal cell model for studying TAU sorting, which is readily accessible at low cost and without animal need, and that ii) the mechanisms of axonal TAU targeting require the TAU C-terminal half but are independent of ANKG or TRIM46 enrichment at the proximal axon.


Neuron ◽  
2020 ◽  
Vol 106 (2) ◽  
pp. 354
Author(s):  
Jone López-Erauskin ◽  
Takahiro Tadokoro ◽  
Michael W. Baughn ◽  
Brian Myers ◽  
Melissa McAlonis-Downes ◽  
...  

2020 ◽  
Author(s):  
Ari W. Schaler ◽  
Avery M. Runyan ◽  
Stephanie L. Fowler ◽  
Helen Y. Figueroa ◽  
Seiji Shioda ◽  
...  

AbstractAccumulation of pathological tau in synapses has been identified as an early pathogenic event in Alzheimer’s disease (AD) and correlates strongly with cognitive decline in patients with AD. Tau is a cytosolic, axonal protein. However, in the disease condition, tau accumulates in post-synaptic compartments and pre-synaptic terminals, either due to missorting within neurons, trans-synaptic transfer between neurons or due to failure of clearance systems in synapses. Using a sub-cellular fractionation assay, we show that progressive deposition of seed competent tau occurs predominantly in post-synaptic compartments in a tau transgenic mouse and in AD patient brain, making these neuronal structures particularly vulnerable to tau toxicity. Tau-mediated post-synaptic toxicity could be further exacerbated by impaired proteasome activity which we detected by measuring the levels of polyubiquitin chains that target proteins to proteasomal degradation. To combat the accumulation of tau and proteasome impairment at the subcellular level, we devised a therapeutic strategy of proteasome-mediated clearance of tau restricted to the post-synaptic compartment. Utilizing the pharmacology of GPCRs, we show that in vivo stimulation of the PAC1R receptor by its ligand can propagate intracellular PKA signaling leading to enhanced synaptic proteasome activity and reduced tau in the post-synaptic compartment. Over time, clearance of post-synaptic tau led to reduced tauopathy and cognitive decline in rTg4510 mice. Together, these results highlight a novel therapeutic strategy of targeting GPCRs that propagate cAMP/PKA signaling as a tool to activate proteolysis restricted to synapses to prevent the accumulation of tau in the early stages of AD.


2020 ◽  
Author(s):  
Emily Scott-Solomon ◽  
Rejji Kuruvilla

SummaryCompartmentalized signaling is critical for cellular organization and specificity of functional outcomes in neurons. Here, we report that post-translational lipidation of newly synthesized proteins in axonal compartments allows for short-term and autonomous responses to extrinsic cues. Using conditional mutant mice, we found that protein prenylation is essential for sympathetic axon innervation of target organs. We identify a localized requirement for prenylation in sympathetic axons to promote axonal growth in response to the neurotrophin, Nerve Growth Factor (NGF). NGF triggers prenylation of proteins including the Rac1 GTPase in axons, counter to the canonical view of prenylation as constitutive, and strikingly, in a manner dependent on axonal protein synthesis. Newly prenylated proteins localize to TrkA-harboring endosomes in axons, and promote receptor trafficking necessary for axonal growth. Thus, coupling of prenylation to local protein synthesis presents a mechanism for spatially segregated cellular functions during neuronal development.


2018 ◽  
Author(s):  
Sunil Goodwani ◽  
Mary E Hamby ◽  
Virginie Buggia-Prevot ◽  
Paul Acton ◽  
Celia Fernandez ◽  
...  

AbstractDual Leucine Zipper Kinase (DLK, Map3k12), is an injury-induced axonal protein that governs the balance between degeneration and regeneration through its downstream effectors c-jun N-terminal kinase (JNK) and phosphorylated c-jun (p-c-Jun). DLK is generally considered to be inactive in healthy neurons until induced by injury. However we report that DLK in the cerebellum appears constitutively active and drives nuclear p-c-Jun in cerebellar granule neurons in the absence of injury. In contrast the adult hippocampus expresses similar levels of apparently constitutively active DLK, but p-c-Jun is lower and does not accumulate in the nucleus. Injury is required there for p-c-jun nuclear expression, because in the rTg4510 model of tauopathy, where there is extensive hippocampal pathology, nuclear p-c-Jun is induced in a DLK-dependent manner. This context-specific regulation of DLK signaling could relate to availability of JNK scaffolding proteins, as the cerebellum preferentially expresses JNK-interacting protein-1 (JIP-1) whereas the hippocampus contains more JIP-3 and Plenty of SH3 (POSH). To understand how DLK signaling differs between the hippocampus and cerebellum, we selectively blocked DLK and measured changes in protein and mRNA expression. In the cerebellum, p-c-Jun levels correlated with synaptophysin, suggesting a link between DLK activity and synaptic maintenance. In rTg4510 mice, hippocampal p-c-Jun instead correlated with markers of neuronal injury and gliosis (Iba1 and GFAP). RNA sequencing revealed that in both brain regions DLK inhibition reduced expression of JNK/c-Jun pathway components and a novel set of co-regulated genes. In the cerebellum, Jun mRNA levels were co-regulated with genes mapping to metabolic pathways, while in the rTg4510 hippocampus, Jun-correlated mRNAs correspond primarily to neuroinflammation. These data suggest that in the uninjured cerebellum, DLK/p-c-Jun signaling is linked to synaptic regulation, but in the hippocampus, pathologically activated DLK/p-c-Jun signaling regulates genes associated with the injury response.


Neuron ◽  
2018 ◽  
Vol 100 (4) ◽  
pp. 816-830.e7 ◽  
Author(s):  
Jone López-Erauskin ◽  
Takahiro Tadokoro ◽  
Michael W. Baughn ◽  
Brian Myers ◽  
Melissa McAlonis-Downes ◽  
...  

2018 ◽  
Author(s):  
Li-An Chu ◽  
Chieh-Han Lu ◽  
Shun-Min Yang ◽  
Kuan-Lin Feng ◽  
Yen-Ting Liu ◽  
...  

AbstractLong-term memory (LTM) formation requires learning-induced protein synthesis in specific neurons and synapses within a neural circuit. Precisely how neural activity allocates new proteins to specific synaptic ensembles, however, remains unknown. We developed a deep-tissue super-resolution imaging tool suitable for single-molecule localization in intact adult Drosophila brain, and focused on the axonal protein allocation in mushroom body (MB), a central neuronal structure involved in olfactory memory formation. We found that insufficient training suppresses LTM formation by inducing the synthesis of vesicular monoamine transporter (VMAT) proteins within a dorsal paired medial (DPM) neuron, which innervates all axonal lobes of the MB. Surprisingly, using our localization microscopy, we found that these learning-induced proteins are distributed only in a subset of DPM axons in specific sectors along the MB lobes. This neural architecture suggests that sector-specific modulation of neural activity from MB neurons gates consolidation of early transient memory into LTM.


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