Loss of tubulin deglutamylase
            <scp>CCP</scp>
            1 causes infantile‐onset neurodegeneration

Shashi, Vandana; Magiera, Maria M.; Klein, Dennis; Zaki, Maha S.; Schoch, Kelly; Rudnik‐Schöneborn, Sabine; Norman, Andrew; Neto, Osorio Lopes Abath; Dusl, Marina; Yuan, Xidi; Bartesaghi, Luca; Marco, Patrizia De; Alfares, Ahmed; Marom, Ronit; Arold, Stefan T.; Guzmán‐Vega, Francisco J.; Peña, Loren; Smith, Edward C.; Steinlin, Maja; Babiker, Mohamed OE; Mohassel, Payam; Foley, A. Reghan; Donkervoort, Sandra; Kaur, Rupleen; Ghosh, Partha S.; Stanley, Valentina; Musaev, Damir; Nava, Caroline; Mignot, Cyril; Keren, Boris; Scala, Marcello; Tassano, Elisa; Picco, Paolo; Doneda, Paola; Fiorillo, Chiara; Issa, Mahmoud Y.; Alassiri, Ali H.; Alahmad, Ahmed; Gerard, Amanda; Liu, Pengfei; Yang, Yaping; Ertl‐Wagner, Birgit; Kranz, Peter G.; Wentzensen, Ingrid M.; Stucka, Rolf; Stong, Nicholas; Allen, Andrew S.; Goldstein, David B.; Schöser, Benedikt; Rösler, Kai M.; Alfadhel, Majid; Capra, Valeria; Chrast, Roman; Strom, Tim M.; Kamsteeg, Erik‐Jan; Bönnemann, Carsten G.; Gleeson, Joseph G.; Martini, Rudolf; Janke, Carsten; Senderek, Jan

doi:10.15252/embj.2018100540

Cited by 97 publications

(166 citation statements)

References 50 publications

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“…Therefore, the study of animal models suffering from cerebellar impairments presents an opportunity for studying the potential use of cell fusion as a therapeutic approach against neurodegenerative diseases. More precisely, certain cerebellar diseases, such as spinocebellar ataxias, are good examples of a fast-onset process of neurodegeneration (Anheim, Tranchant, & Koenig, 2012;de Assis Franco et al, 2018;Karakaya et al, 2019;Shashi et al, 2018;Sheffer et al, 2019).…”

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confidence: 99%

Daily bone marrow cell transplantations for the management of fast neurodegenerative processes

Díaz

Pilar

Carretero

et al. 2019

J Tissue Eng Regen Med

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Cell therapy has been proven to be a promising treatment for fighting neurodegenerative diseases. As neuronal replacement presents undeniable complications, the neuroprotection of live neurons arises as the most suitable therapeutic approach. Accordingly, the earlier the diagnosis and treatment, the better the prognosis. However, these diseases are commonly diagnosed when symptoms have already progressed towards an irreversible degenerative stage. This problem is especially dramatic when neurodegeneration is aggressive and rapidly progresses. One of the most interesting approaches for neuroprotection is the fusion between healthy bone marrow‐derived cells and neurons, as the former can provide the latter with regular/protective genes without harming brain parenchyma. So far, this phenomenon has only been identified in Purkinje cells, whose death is the cause of different diseases like cerebellar ataxias. Here we have employed a model of aggressive cerebellar neurodegeneration, the Purkinje Cell Degeneration mouse, to optimize a cell therapy based on bone marrow‐derived cell and cell fusion. Our findings show that the substitution of bone marrow in diseased animals by healthy bone marrow, even prior to the onset of neurodegeneration, is not fast enough to stop neuronal loss in time. Conversely, avoiding bone marrow replacement and ensuring a regular supply of healthy cells through continuous, daily transplants, the neurodegenerative milieu of PCD is enough to attract those transplanted elements. Furthermore, in the most affected cerebellar regions, more than a half of surviving neurons undergo a process of cell fusion. Therefore, this method deserves consideration as a means to impede neuronal cell death.

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confidence: 99%

Daily bone marrow cell transplantations for the management of fast neurodegenerative processes

Díaz

Pilar

Carretero

et al. 2019

J Tissue Eng Regen Med

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“…The genes identified herein are associated with human disorders. Loss of CCP1 causes retinal dystrophy, and the infantile-onset neurodegeneration of cerebellar neurons, spinal motor neurons, and peripheral nerves [70,71]. Glutamylation may also play an important role in ciliopathies including Joubert Syndrome [72] and hereditary retinal degeneration [24].…”

Section: Discussionmentioning

confidence: 99%

Mutation of NEKL-4/NEK10 and TTLL genes opposes loss of the CCPP-1 deglutamylase and prevents neuronal ciliary degeneration

Power¹,

Akella²,

Gu³

et al. 2020

Preprint

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Ciliary microtubules are subject to post-translational modifications that act as a "Tubulin Code" to regulate motor traffic, binding proteins and stability. In humans, loss of CCP1, a cytosolic carboxypeptidase and tubulin deglutamylating enzyme, causes infantile-onset neurodegeneration. In C. elegans, mutations in ccpp-1, the homolog of CCP1, result in progressive degeneration of neuronal cilia and loss of neuronal function. To identify genes that regulate microtubule glutamylation and ciliary integrity, we performed a forward genetic screen for suppressors of ciliary degeneration in ccpp-1 mutants. We isolated the ttll-5(my38) suppressor, a mutation in the tubulin tyrosine ligase-like glutamylase gene. We show that mutation in ttll-4, ttll-5, or ttll-11 gene suppressed the hyperglutamylation-induced loss of microtubules and kinesin-2 mislocalization in ccpp-1 cilia. We also identified the nekl-4(my31) suppressor, an allele affecting the NIMA (Never in Mitosis A)-related kinase NEKL-4/NEK10. In humans, NEK10 mutation causes bronchiectasis, an airway and mucociliary transport disorder caused by defective motile cilia. C. elegans NEKL-4 does not localize to cilia yet plays a role in regulating axonemal microtubule stability. This work defines a pathway in which glutamylation, a component of the Tubulin Code, is written by TTLL-4, TTLL-5, and TTLL-11; is erased by CCPP-1; is read by ciliary kinesins; and its downstream effects are modulated by NEKL-4 activity. Identification of regulators of microtubule glutamylation in diverse cellular contexts is important to the development of effective therapies for disorders characterized by changes in microtubule glutamylation. By identifying C. elegans genes important for neuronal and ciliary stability, our work may inform research into human ciliopathies and neurodegenerative diseases.

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“…Next, we examined whether accumulation of D2 was necessary for Bort-induced axonopathy. Lentiviral mediated depletion of CCP1 in differentiated adult DRG neurons promoted substantial loss of D2 with only negligible effects on polyglutamylated tubulin levels, a tubulin PTM recently implicated in neurodegeneration that is negatively regulated by the tubulin deglutamylating activity of CCP1 29,46 (Fig. S5F).…”

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confidence: 92%

“…Furthermore, tubulin and MTs functionally interact with TRPV1 22,23 , and -tubulin acetylation appears to be a critical component of the mammalian mechano-transduction machinery 24 . Importantly, anomalies in MT dynamics and tubulin PTMs can drive axon regeneration failure and neurodegeneration [24][25][26][27][28][29][30][31][32] .…”

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confidence: 99%

Pathogenic Role of Delta 2 Tubulin in Bortezomib Induced Peripheral Neuropathy

Pero

Meregalli

et al. 2019

Preprint

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The pathogenesis of chemotherapy induced peripheral neuropathy (CIPN) is still poorly understood. Herein, we found that the CIPN-causing drug, bortezomib (Bort), induces delta 2 tubulin (D2) while affecting MT stability and dynamics in sensory neurons, and that accumulation of D2 is a hallmark of Bort-induced peripheral neuropathy in humans. Furthermore, while induction of D2 was sufficient to cause axonopathy and inhibit mitochondria motility, reducing D2 alleviated both axonal degeneration and loss of mitochondria motility promoted by Bort. Altogether, our data demonstrate that Bort, structurally unrelated to tubulin poisons, can affect the tubulin cytoskeleton in sensory neurons in vitro, in vivo and in humans, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. They further reveal a previously unrecognized pathogenic role for D2 in bortezomibcausing CIPN through its regulation of mitochondria dynamics.

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Loss of tubulin deglutamylase CCP 1 causes infantile‐onset neurodegeneration

Cited by 97 publications

References 50 publications

Daily bone marrow cell transplantations for the management of fast neurodegenerative processes

Daily bone marrow cell transplantations for the management of fast neurodegenerative processes

Mutation of NEKL-4/NEK10 and TTLL genes opposes loss of the CCPP-1 deglutamylase and prevents neuronal ciliary degeneration

Pathogenic Role of Delta 2 Tubulin in Bortezomib Induced Peripheral Neuropathy

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