ArticleScientific reports2021
Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 19 citations in OpenAlex.
- Phenotypic and molecular characterization of a recurrent SPTAN1 mutation causing SPG91.Molecular biology reports · 2025Article
- Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteins.Experimental biology and medicine (Maywood, N.J.) · 2025Review
- Optical biosensors for diagnosing neurodegenerative diseases.Npj biosensing · 2025Review
- The loss of βΙ spectrin alters synaptic size and composition in theFrontiers in neuroscience · 2024Article
- A kinesin-1 adaptor complex controls bimodal slow axonal transport of spectrin in Caenorhabditis elegans.Developmental cell · 2023Article
- Spectrins: molecular organizers and targets of neurological disorders.Nature reviews. Neuroscience · 2023Review
- Roles of the cytoskeleton in human diseases.Molecular biology reports · 2023Review
- Progressive Ataxia, Memory Impairments, and Seizure Episodes inBrain sciences · 2023Article
- Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.Movement disorders : official journal of the Movement Disorder Society · 2022Article
- Membrane lipid raft homeostasis is directly linked to neurodegeneration.Essays in biochemistry · 2021Review
- The Spread of Spectrin in Ataxia and Neurodegenerative Disease.Journal of experimental neurology · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
The neuronal membrane-associated periodic spectrin skeleton (MPS) contributes to neuronal development, remodeling, and organization. Post-translational modifications impinge on spectrin, the major component of the MPS, but their role remains poorly understood. One modification targeting spectrin is cleavage by calpains, a family of calcium-activated proteases. Spectrin cleavage is regulated by activated calpain, but also by the calcium-dependent binding of calmodulin (CaM) to spectrin. The physiologic significance of this balance between calpain activation and substrate-level regulation of spectrin cleavage is unknown. We report a strain of C57BL/6J mice harboring a single αII spectrin point mutation (Sptan1 c.3293G > A:p.R1098Q) with reduced CaM affinity and intrinsically enhanced sensitivity to calpain proteolysis. Homozygotes are embryonic lethal. Newborn heterozygotes of either gender appear normal, but soon develop a progressive ataxia characterized biochemically by accelerated calpain-mediated spectrin cleavage and morphologically by disruption of axonal and dendritic integrity and global neurodegeneration. Molecular modeling predicts unconstrained exposure of the mutant spectrin's calpain-cleavage site. These results reveal the critical importance of substrate-level regulation of spectrin cleavage for the maintenance of neuronal integrity. Given that excessive activation of calpain proteases is a common feature of neurodegenerative disease and traumatic encephalopathy, we propose that damage to the spectrin MPS may contribute to the neuropathology of many disorders.
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