ArticleJCI insight2020
Nna1 gene deficiency triggers Purkinje neuron death by tubulin hyperglutamylation and ER dysfunction.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- Targeting TTLL1 Alleviates Aβ-Induced Microtubule Disruption and TAU Pathology in Human iPSC-Derived Cortical Neurons.Pharmaceutics · 2026Article
- Single-Cell RNA Sequencing of Retina Reveals Nna1 Upregulation in Myopic Diabetic Retinopathy as a Protective Factor Against Diabetic Damage.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Spatial transcriptomics analysis uncovers ER stress in MANF-deficient Purkinje cells underlying alcohol-induced cerebellar neurodegeneration in mice.Acta neuropathologica communications · 2025Article
- Cell replacement in the degenerating cerebellum: a historical essay of discovery.Journal of neurology · 2025Review
- AAV-based gene therapy ameliorates neurological deficits in a mouse model of childhood-onset neurodegeneration with cerebellar atrophy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons.The Journal of cell biology · 2024Article
- NEKL-4 regulates microtubule stability and mitochondrial health inbioRxiv : the preprint server for biology · 2024Article
- [Expression of TUBB4B in mouse primary spermatocyte GC-2 cells and its regulatory effect on NF-κB and MAPK signaling pathway].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2023Article
- Oleoylethanolamide Treatment Modulates Both Neuroinflammation and Microgliosis, and Prevents Massive Leukocyte Infiltration to the Cerebellum in a Mouse Model of Neuronal Degeneration.International journal of molecular sciences · 2023Article
- Microtubule acetylation dyshomeostasis in Parkinson's disease.Translational neurodegeneration · 2023Review
- CCP1, a Regulator of Tubulin Post-Translational Modifications, Potentially Plays an Essential Role in Cerebellar Development.International journal of molecular sciences · 2023Article
- Polyglutamylation: biology and analysis.Amino acids · 2022Review
- The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused byBiomedicines · 2021Review
- Oleoylethanolamide Delays the Dysfunction and Death of Purkinje Cells and Ameliorates Behavioral Defects in a Mouse Model of Cerebellar Neurodegeneration.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Posttranslational glutamylation/deglutamylation balance in tubulins influences dendritic maturation and neuronal survival of cerebellar Purkinje neurons (PNs). PNs and some additional neuronal types degenerate in several spontaneous, independently occurring Purkinje cell degeneration (pcd) mice featuring mutant neuronal nuclear protein induced by axotomy (Nna1), a deglutamylase gene. This defective deglutamylase allows glutamylases to form hyperglutamylated tubulins. In pcd, all PNs die during postnatal "adolescence." Neurons in some additional brain regions also die, mostly later than PNs. We show in laser capture microdissected single PNs, in cerebellar granule cell neuronal clusters, and in dissected hippocampus and substantia nigra that deglutamase mRNA and protein were virtually absent before pcd PNs degenerated, whereas glutaminase mRNA and protein remained normal. Hyperglutamylated microtubules and dimeric tubulins accumulated in pcd PNs and were involved in pcd PN death by glutamylase/deglutamylase imbalance. Importantly, treatment with a microtubule depolymerizer corrected the glutamylation/deglutamylation ratio, increasing PN survival. Further, before onset of neuronal death, pcd PNs displayed prominent basal polylisosomal masses rich in ER. We propose a "seesaw" metamorphic model summarizing mutant Nna1-induced tubulin hyperglutamylation, the pcd's PN phenotype, and report that the neuronal disorder involved ER stress, unfolded protein response, and protein synthesis inhibition preceding PN death by apoptosis/necroptosis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.