Combined kinesin-1 and kinesin-3 activity drives axonal trafficking of TrkB receptors in Rab6 carriers

A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell–derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. Cargo transport defects are recapitulated by treating neurons from healthy individuals with proline-arginine and glycine-arginine dipeptide repeats (DPRs) produced from the repeat expansion. Both arginine-rich DPRs similarly inhibit axonal trafficking in adult Drosophila neurons in vivo. Physical interaction studies demonstrate that arginine-rich DPRs associate with motor complexes and the unstructured tubulin tails of microtubules. Single-molecule imaging reveals that microtubule-bound arginine-rich DPRs directly impede translocation of purified dynein and kinesin-1 motor complexes. Collectively, our study implicates inhibitory interactions of arginine-rich DPRs with axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to potential therapeutic strategies.

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TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713969114 ◽

2017 ◽

Vol 114 (40) ◽

pp. 10773-10778 ◽

Cited By ~ 40

Author(s):

Seong Su Kang ◽

Zhentao Zhang ◽

Xia Liu ◽

Fredric P. Manfredsson ◽

Matthew J. Benskey ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuronal Death ◽

Kinase Domain ◽

Alpha Synuclein ◽

Mao B ◽

Protein Levels ◽

Trkb Receptors ◽

Alpha Synuclein Aggregation ◽

Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

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Brain ischaemia induces shedding of a BDNF-scavenger ectodomain from TrkB receptors by excitotoxicity activation of metalloproteinases and γ-secretases

The Journal of Pathology ◽

10.1002/path.4684 ◽

2016 ◽

Vol 238 (5) ◽

pp. 627-640 ◽

Cited By ~ 15

Author(s):

Gonzalo S Tejeda ◽

Sara Ayuso-Dolado ◽

Raquel Arbeteta ◽

Gema M Esteban-Ortega ◽

Oscar G Vidaurre ◽

...

Keyword(s):

Brain Ischaemia ◽

Trkb Receptors

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BDNF-Induced Facilitation of Afferent-Evoked Responses in Lamina II Neurons Is Reduced After Neonatal Spinal Cord Contusion Injury

Journal of Neurophysiology ◽

10.1152/jn.00179.2005 ◽

2005 ◽

Vol 94 (3) ◽

pp. 1798-1804 ◽

Cited By ~ 16

Author(s):

Sandra M. Garraway ◽

Aileen J. Anderson ◽

Lorne M. Mendell

Keyword(s):

Nmda Receptor ◽

Dorsal Root ◽

Dependent Manner ◽

Evoked Responses ◽

Patch Clamp Technique ◽

Synaptic Facilitation ◽

Trkb Receptors ◽

Contusion Injury ◽

Nmda Receptor Function ◽

Spinal Cord Contusion

We previously reported that brain-derived neurotrophic factor (BDNF), a pronociceptive neurotransmitter, induces synaptic facilitation of excitatory postsynaptic current (EPSC) in lamina II neurons of neonatal rats up to P14 in a N-methyl-d-aspartate (NMDA) receptor-dependent manner. Here we used the patch-clamp technique to study synaptic and NMDA-evoked responses in transverse spinal slices in the lumbar enlargement as well as the ability of BDNF to modify these responses from 1 day to 6 wk after neonatal contusion. In older uninjured animals (>P14), BDNF continued to evoke synaptic facilitation although superfusion of NMDA (in TTX) induced inward current of significantly smaller amplitude than that observed in younger rats. After contusion injury, BDNF was unable to facilitate dorsal root-evoked EPSCs in lamina II neurons despite the finding that NMDA-evoked currents were only slightly smaller than those observed in age-matched uninjured animals. These findings suggest that although BDNF-induced facilitation of the AMPA/kainate receptor-mediated response to dorsal root stimulation is maintained in the mature dorsal horn from intact rats, BDNF may no longer elicit these pronociceptive actions after neonatal contusion injury. The lack of change in NMDA-evoked currents in contused cords suggests that diminished NMDA receptor function is not the major cause of the decline in BDNF action after contusion. It seems more likely that diminished trkB expression and enhanced expression of truncated trkB receptors in the contused cord play a significant role in determining the reduced effect of BDNF under these conditions.

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845. Disruption of the Axonal Trafficking of Tyrosine Hydroxylase mRNA Impairs Catecholamine Biosynthesis in the Axons of Sympathetic Neurons

Biological Psychiatry ◽

10.1016/j.biopsych.2017.02.570 ◽

2017 ◽

Vol 81 (10) ◽

pp. S342

Author(s):

Armaz Aschrafi ◽

Anthony E Gioio ◽

Lijin Dong ◽

Barry Kaplan

Keyword(s):

Tyrosine Hydroxylase ◽

Sympathetic Neurons ◽

Catecholamine Biosynthesis ◽

Axonal Trafficking

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Activation of endothelial TrkB receptors induces relaxation of resistance arteries

Vascular Pharmacology ◽

10.1016/j.vph.2018.02.005 ◽

2018 ◽

Vol 106 ◽

pp. 46-53 ◽

Cited By ~ 4

Author(s):

P. Totoson ◽

M. Pedard ◽

C. Marie ◽

C. Demougeot

Keyword(s):

Resistance Arteries ◽

Trkb Receptors

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Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer’s disease trigger BACE1 accumulation in axonal swellings

Science Translational Medicine ◽

10.1126/scitranslmed.aba1871 ◽

2020 ◽

Vol 12 (570) ◽

pp. eaba1871

Author(s):

Selene Lomoio ◽

Rachel Willen ◽

WonHee Kim ◽

Kevin Z. Ho ◽

Edward K. Robinson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variant ◽

Late Onset ◽

Early Stage ◽

Loss Of Function ◽

Axonal Trafficking ◽

Axonal Swellings

Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer’s disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 genetic deletion or a GGA3 rare variant that cosegregates with late-onset AD, disrupts the axonal trafficking of the β-site APP-cleaving enzyme 1 (BACE1) resulting in its accumulation in axonal swellings in cultured neurons and in vivo. We show that BACE pharmacological inhibition ameliorates BACE1 axonal trafficking and diminishes axonal dystrophies in Gga3 null neurons in vitro and in vivo. These data indicate that axonal accumulation of BACE1 engendered by GGA3 loss of function results in local toxicity leading to axonopathy. Gga3 deletion exacerbates axonal dystrophies in a mouse model of AD before β-amyloid (Aβ) deposition. Our study strongly supports a role for GGA3 in AD pathogenesis, where GGA3 loss of function triggers BACE1 axonal accumulation independently of extracellular Aβ, and initiates a cascade of events leading to the axonal damage distinctive of the early stage of AD.

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Neurotrophin signalling in amygdala-dependent cued fear learning

Cell and Tissue Research ◽

10.1007/s00441-020-03260-3 ◽

2020 ◽

Vol 382 (1) ◽

pp. 161-172 ◽

Cited By ~ 1

Author(s):

Susanne Meis ◽

Thomas Endres ◽

Volkmar Lessmann

Keyword(s):

Synaptic Plasticity ◽

Learning And Memory ◽

Neurotrophic Factor ◽

Memory Formation ◽

Fear Learning ◽

Mammalian Brain ◽

Pavlovian Fear Conditioning ◽

Cortical Afferents ◽

Trkb Receptors ◽

Tropomyosin Related Kinase B

Abstract The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced.

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