Biallelic variant in <i>AGTPBP1</i> causes infantile lower motor neuron degeneration and cerebellar atrophy

Karakaya, Mert; Paketçi, Cem; Altmueller, Janine; Thiele, Holger; Hoelker, Irmgard; Yış, Uluç; Wirth, Brunhilde

doi:10.1002/ajmg.a.61198

Cited by 33 publications

(34 citation statements)

References 10 publications

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“…Taken together, all of these findings allow us to propose that the daily transplant of bone marrow stem cells could be a promising method for cell therapy against aggressive neurodegenerations, and of interest to those researchers studying this type of disease. Moreover, this therapeutic approach can be especially interesting for dealing with infantile human cerebellar impairments, also sharing the genotypic features and symptoms of PCD mice (Karakaya et al, ; Shashi et al, ; Sheffer et al, ). However, further work is required to improve the use of this strategy for cell rescue, either by cell fusion or by the release of neuroprotective factors.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, PCD mice suffer a dramatic Purkinje cell loss that begins around postnatal day 18 (P18) and progresses rapidly over the next 2 weeks, until virtually all of these neurons have disappeared at around P40 (Mullen, Eicher, & Sidman, ; Wang & Morgan, ). Moreover, the pcd mutation causes the lack of expression of the Agtpbp1 gene (also known as Nna1 or Ccp1 ), which can origin early‐onset and aggressive human cerebellar impairments (Karakaya et al, ; Shashi et al, ; Sheffer et al, ). Therefore, the PCD mouse offers a suitable model for the study of fast neurodegeneration that can be used as a demanding trial for cell therapies.…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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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 discovery of a novel infant-onset human condition linked to inactivating mutations in CCP1 with remarkable similarity to the pcd mouse model [234][235][236] established deregulated polyglutamylation as a novel cause of human neurodegeneration. It is conceivable that more subtle alterations of this PTM could be linked, or even causative, for other, late-onset human pathologies.…”

Section: 2) Functions Of Tubulin Ptms In Neuronsmentioning

confidence: 99%

The tubulin code and its role in controlling microtubule properties and functions

Janke

Magiera

2020

Nat Rev Mol Cell Biol

513

440

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Microtubules are core components of the eukaryotic cytoskeleton with essential roles in cell division, shaping, intracellular transport, and motility. Despite their functional heterogeneity, microtubules have a highly conserved structure made from almost identical molecular building blocks; the tubulin proteins. Alternative tubulin isotypes and a variety of posttranslational modifications control the properties and functions of the microtubule cytoskeleton, a concept known as the 'tubulin code'. This concept first emerged with the discovery that α-and β-tubulin are each encoded by multiple genes, but it took decades before its functional importance begun to emerge. Here we review the current understanding of the molecular components of the tubulin code, and how they impact microtubule properties and functions. We discuss how tubulin isotypes and posttranslational modifications control microtubule behaviour at the molecular level, and how this translates into physiological functions at the cellular and organism levels. We further show how the fine-tuning of microtubule functions by some tubulin modifications affects homeostasis, and how its perturbation can lead to a large variety of dysfunctions, many of them linked to human disorders.

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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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Biallelic variant in AGTPBP1 causes infantile lower motor neuron degeneration and cerebellar atrophy

Cited by 33 publications

References 10 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

The tubulin code and its role in controlling microtubule properties and functions

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

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