Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss during Neuromuscular Synapse Elimination

Brill, Monika S.; Kleele, Tatjana; Ruschkies, Laura; Wang, Mengzhe; Marahori, Natalia A.; Reuter, Miriam S.; Hausrat, Torben J.; Weigand, Emily E.; Fisher, Mike; Ahles, Andrea; Engelhardt, Stefan; Bishop, Derron L.; Kneussel, Matthias; Misgeld, Thomas

doi:10.1016/j.neuron.2016.09.049

Cited by 92 publications

(157 citation statements)

References 76 publications

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“…At 5 h APF, when most dendrites are still attached to the soma, clear gaps in the GFP::a-tubulin were visible in the proximal dendrites, indicating the loss of microtubules ( Fig 2B and B 0 ). Microtubule stability and dynamics can be assessed by looking at microtubule posttranslational modifications (Brill et al, 2016;Tao et al, 2016). Microtubule stability and dynamics can be assessed by looking at microtubule posttranslational modifications (Brill et al, 2016;Tao et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

PAR‐1 promotes microtubule breakdown during dendrite pruning in Drosophila

et al. 2017

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Pruning of unspecific neurites is an important mechanism during neuronal morphogenesis. sensory neurons prune their dendrites during metamorphosis. Pruning dendrites are severed in their proximal regions. Prior to severing, dendritic microtubules undergo local disassembly, and dendrites thin extensively through local endocytosis. Microtubule disassembly requires a katanin homologue, but the signals initiating microtubule breakdown are not known. Here, we show that the kinase PAR-1 is required for pruning and dendritic microtubule breakdown. Our data show that neurons lacking PAR-1 fail to break down dendritic microtubules, and PAR-1 is required for an increase in neuronal microtubule dynamics at the onset of metamorphosis. Mammalian PAR-1 is a known Tau kinase, and genetic interactions suggest that PAR-1 promotes microtubule breakdown largely via inhibition of Tau also in Finally, PAR-1 is also required for dendritic thinning, suggesting that microtubule breakdown might precede ensuing plasma membrane alterations. Our results shed light on the signaling cascades and epistatic relationships involved in neurite destabilization during dendrite pruning.

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Section: Resultsmentioning

confidence: 99%

PAR‐1 promotes microtubule breakdown during dendrite pruning in Drosophila

et al. 2017

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“…Most notably, there was progressive slowing of large fiber MNCV that was prevented by J147 when given from the onset of diabetes. Nerve conduction slowing is widely used in the diagnosis and staging of diabetic neuropathy and serves as the primary quantifiable endpoint in clinical trials of drugs to treat this condition (Bril, 2016; Brill et al, 2016). Diverse pathogenic mechanisms have been proposed from preclinical studies including polyol pathway flux, ischemic hypoxia, oxidative stress, inflammation and loss of neurotrophic support (Yagihashi, 2016).…”

Section: Discussionmentioning

confidence: 99%

A novel curcumin derivative for the treatment of diabetic neuropathy

et al. 2018

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Neuropathy is a common complication of long-term diabetes. Proposed mechanisms of neuronal damage caused by diabetes that are downstream of hyperglycemia and/or loss of insulin signaling include ischemic hypoxia, inflammation and loss of neurotrophic support. The curcumin derivative J147 is a potent neurogenic and neuroprotective drug candidate initially developed for the treatment of neurodegenerative conditions associated with aging that impacts many pathways implicated in the pathogenesis of diabetic neuropathy. Here, we demonstrate efficacy of J147 in ameliorating multiple indices of neuropathy in the streptozotocin-induced mouse model of type 1 diabetes. Diabetes was determined by blood glucose, HbA1c, and insulin levels and efficacy of J147 by behavioral, physiologic, biochemical, proteomic, and transcriptomic assays. Biological efficacy of systemic J147 treatment was confirmed by its capacity to decrease TNFα pathway activation and several other markers of neuroinflammation in the CNS. Chronic oral treatment with J147 protected the sciatic nerve from progressive diabetes-induced slowing of large myelinated fiber conduction velocity while single doses of J147 rapidly and transiently reversed established touch-evoked allodynia. Conduction slowing and allodynia are clinically relevant markers of early diabetic neuropathy and neuropathic pain, respectively. RNA expression profiling suggests that one of the pathways by which J147 imparts its protection against diabetic induced neuropathy may be through activation of the AMP kinase pathway. The diverse biological and therapeutic effects of J147 suggest it as an alternative to the polypharmaceutical approaches required to treat the multiple pathogenic mechanisms that contribute to diabetic neuropathy.

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“…pcd mice (BALB/cByJ-Agtpbp1 pcdÀ3J /J; www.jax.org/strain/ 003237) were obtained from the Jackson Laboratory. Spastin À/À mice were described before (Brill et al, 2016). Ttll1 tm1a(EUCOMM)Wtsi mice were generated at EUCOMM (http://www.mousephenotype.org/da ta/alleles/MGI:2443047/tm1a(EUCOMM)Wtsi).…”

Section: Mouse Lines and Genotyping And Breedingmentioning

confidence: 99%

Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport

et al. 2018

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Posttranslational modifications of tubulin are emerging regulators of microtubule functions. We have shown earlier that upregulated polyglutamylation is linked to rapid degeneration of Purkinje cells in mice with a mutation in the deglutamylating enzyme CCP1. How polyglutamylation leads to degeneration, whether it affects multiple neuron types, or which physiological processes it regulates in healthy neurons has remained unknown. Here, we demonstrate that excessive polyglutamylation induces neurodegeneration in a cell‐autonomous manner and can occur in many parts of the central nervous system. Degeneration of selected neurons in CCP1‐deficient mice can be fully rescued by simultaneous knockout of the counteracting polyglutamylase TTLL1. Excessive polyglutamylation reduces the efficiency of neuronal transport in cultured hippocampal neurons, suggesting that impaired cargo transport plays an important role in the observed degenerative phenotypes. We thus establish polyglutamylation as a cell‐autonomous mechanism for neurodegeneration that might be therapeutically accessible through manipulation of the enzymes that control this posttranslational modification.

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Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss during Neuromuscular Synapse Elimination

Cited by 92 publications

References 76 publications

PAR‐1 promotes microtubule breakdown during dendrite pruning in Drosophila

PAR‐1 promotes microtubule breakdown during dendrite pruning in Drosophila

A novel curcumin derivative for the treatment of diabetic neuropathy

Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport

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