BDNF/trkB Induction of Calcium Transients through Cav2.2 Calcium Channels in Motoneurons Corresponds to F-actin Assembly and Growth Cone Formation on β2-Chain Laminin (221)

Dombert, Benjamin; Balk, Stefanie; Lüningschrör, Patrick; Moradi, Mehri; Sivadasan, Rajeeve; Saal-Bauernschubert, Lena; Jablonka, Sibylle

doi:10.3389/fnmol.2017.00346

Cited by 30 publications

(27 citation statements)

References 148 publications

(212 reference statements)

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“…TrkB and its ligand, brain-derived neurotrophic factor (BDNF), play an important role in NMJ synapse elimination 57 – 59 . This may, in part, be driven by BDNF-mediated clustering in motor nerve terminals of voltage-gated calcium channels, which facilitate calcium influx, synaptic neurotransmission, and NMJ maturation 60 – 63 . Mutant GlyRS mis-interacting with TrkB at the NMJ could delay synapse elimination through impairing calcium channel insertion into pre-synaptic motor terminals, thereby hindering neurotransmission and neuronal activity.…”

Section: Discussionmentioning

confidence: 99%

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

2020

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Dominantly inherited, missense mutations in the widely expressed housekeeping gene, GARS1, cause Charcot-Marie-Tooth type 2D (CMT2D), a peripheral neuropathy characterised by muscle weakness and wasting in limb extremities. Mice modelling CMT2D display early and selective neuromuscular junction (NMJ) pathology, epitomised by disturbed maturation and neurotransmission, leading to denervation. Indeed, the NMJ disruption has been reported in several different muscles; however, a systematic comparison of neuromuscular synapses from distinct body locations has yet to be performed. We therefore analysed NMJ development and degeneration across five different wholemount muscles to identify key synaptic features contributing to the distinct pattern of neurodegeneration in CMT2D mice. Denervation was found to occur along a distal-to-proximal gradient, providing a cellular explanation for the greater weakness observed in mutant Gars hindlimbs compared with forelimbs. Nonetheless, muscles from similar locations and innervated by axons of equivalent length showed significant differences in neuropathology, suggestive of additional factors impacting on site-specific neuromuscular degeneration. Defective NMJ development preceded and associated with degeneration, but was not linked to a delay of wild-type NMJ maturation processes. Correlation analyses indicate that muscle fibre type nor synaptic architecture explain the differential denervation of CMT2D NMJs, rather it is the extent of post-natal synaptic growth that predisposes to neurodegeneration. Together, this work improves our understanding of the mechanisms driving synaptic vulnerability in CMT2D and hints at pertinent pathogenic pathways.

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Section: Discussionmentioning

confidence: 99%

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

2020

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“…Additionally, the medium and associated supplements in which DRG neurons were cultured vary across studies. Neuronal activity can impact the rate and quantity of axonal transport (Sajic et al, 2013 ; Wang et al, 2016 ), while proteins such as neurotrophic factors, which are present in primary neuron media, can affect neuronal activity (Dombert et al, 2017 ). Though unlikely, it is possible therefore that the medium in which our neurons were grown may have selectively enhanced Gars C201R/+ transport masking a trafficking deficiency.…”

Section: Discussionmentioning

confidence: 99%

Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels

Sleigh

Mech

Aktar

et al. 2020

Front. Cell. Neurosci.

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Dominant, missense mutations in the widely and constitutively expressed GARS1 gene cause peripheral neuropathy that usually begins in adolescence and principally impacts the upper limbs. Caused by a toxic gain-of-function in the encoded glycyl-tRNA synthetase (GlyRS) enzyme, the neuropathology appears to be independent of the canonical role of GlyRS in aminoacylation. Patients display progressive, life-long weakness and wasting of muscles in hands followed by feet, with frequently associated deficits in sensation. When dysfunction is observed in motor and sensory nerves, there is a diagnosis of Charcot-Marie-Tooth disease type 2D (CMT2D), or distal hereditary motor neuropathy type V if the symptoms are purely motor. The cause of this varied sensory involvement remains unresolved, as are the pathomechanisms underlying the selective neurodegeneration characteristic of the disease. We have previously identified in CMT2D mice that neuropathy-causing Gars mutations perturb sensory neuron fate and permit mutant GlyRS to aberrantly interact with neurotrophin receptors (Trks). Here, we extend this work by interrogating further the anatomy and function of the CMT2D sensory nervous system in mutant Gars mice, obtaining several key results: (1) sensory pathology is restricted to neurons innervating the hindlimbs; (2) perturbation of sensory development is not common to all mouse models of neuromuscular disease; (3) in vitro axonal transport of signaling endosomes is not impaired in afferent neurons of all CMT2D mouse models; and (4) Gars expression is selectively elevated in a subset of sensory neurons and linked to sensory developmental defects. These findings highlight the importance of comparative neurological assessment in mouse models of disease and shed light on key proposed neuropathogenic mechanisms in GARS1 -linked neuropathy.

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“…TrkB and its ligand, brainderived neurotrophic factor (BDNF), play an important role in synapse elimination at the NMJ [53][54][55] . This may, in part, be driven by BDNF-mediated clustering in motor nerve terminals of voltagegated calcium channels, which facilitate calcium influx, synaptic neurotransmission, and NMJ maturation [56][57][58][59] . Mutant GlyRS misinteracting with TrkB at the NMJ could delay synapse elimination through impairing calcium channel insertion into pre-synaptic motor terminals, thereby hindering neurotransmission and neuronal activity.…”

Section: Discussionmentioning

confidence: 99%

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Sleigh

Mech

Schiavo

2020

Preprint

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Dominantly inherited, missense mutations in the widely expressed housekeeping gene, GARS1, cause Charcot-Marie-Tooth type 2D (CMT2D), a peripheral neuropathy characterised by muscle weakness and wasting in limb extremities. Mice modelling CMT2D display early and selective neuromuscular junction (NMJ) pathology, epitomised by disturbed maturation and neurotransmission, leading to denervation. Indeed, the NMJ disruption has been reported in several different muscles; however, a systematic comparison of neuromuscular synapses from distinct body locations has yet to be performed. We therefore analysed NMJ development and degeneration across five different wholemount muscles to identify key synaptic features contributing to the distinct pattern of neurodegeneration in CMT2D mice. Denervation was found to occur along a distal-to-proximal gradient, providing a cellular explanation for the greater weakness observed in mutant Gars hindlimbs compared to forelimbs. Nonetheless, muscles from similar locations and innervated by axons of equivalent length showed significant differences in neuropathology, suggestive of additional factors impacting on sitespecific neuromuscular degeneration. Defective NMJ development preceded and associated with degeneration, but was not linked to a delay of wild-type NMJ maturation processes. Correlation analyses indicate that muscle fibre type nor synaptic architecture explain the differential denervation of CMT2D NMJs, rather it is the extent of post-natal synaptic growth that predisposes to neurodegeneration. Together, this work improves our understanding of the mechanisms driving synaptic vulnerability in CMT2D and hints at pertinent pathogenic pathways.

show abstract

BDNF/trkB Induction of Calcium Transients through Cav2.2 Calcium Channels in Motoneurons Corresponds to F-actin Assembly and Growth Cone Formation on β2-Chain Laminin (221)

Cited by 30 publications

References 148 publications

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

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