Commentary Open Access
Volume 2 | Issue 3 | DOI: https://doi.org/10.33696/Neurol.2.045

The Spread of Spectrin in Ataxia and Neurodegenerative Disease

  • 1Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA
  • 2Molecular & Cellular Developmental Biology, Yale University, New Haven, CT 06520, USA
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Corresponding Author

Jon S. Morrow, jon.morrow@yale.edu

Michael Stankewich, michael.stankewich@yale.edu

Received Date: June 01, 2021

Accepted Date: July 26, 2021


Experimental and hereditary defects in the ubiquitous scaffolding proteins of the spectrin gene family cause an array of neuropathologies. Most recognized are ataxias caused by missense, deletions, or truncations in the SPTBN2 gene that encodes beta III spectrin. Such mutations disrupt the organization of post-synaptic receptors, their active transport through the secretory pathway, and the organization and dynamics of the actin-based neuronal skeleton. Similar mutations in SPTAN1 that encodes alpha II spectrin cause severe and usually lethal neurodevelopmental defects including one form of early infantile epileptic encephalopathy type 5 (West syndrome). Defects in these and other spectrins are implicated in degenerative and psychiatric conditions. In recent published work, we describe in mice a novel variant of alpha II spectrin that results in a progressive ataxia with widespread neurodegenerative change. The action of this variant is distinct, in that rather than disrupting a constitutive ligand-binding function of spectrin, the mutation alters its response to calcium and calmodulin-regulated signaling pathways including its response to calpain activation. As such, it represents a novel spectrinopathy that targets a key regulatory pathway where calcium and tyrosine kinase signals converge. Here we briefly discuss the various roles of spectrin in neuronal processes and calcium activated regulatory inputs that control its participation in neuronal growth, organization, and remodeling. We hypothesize that damage to the neuronal spectrin scaffold may be a common final pathway in many neurodegenerative disorders. Targeting the pathways that regulate spectrin function may thus offer novel avenues for therapeutic intervention.


Membrane-associated periodic skeleton, Calpain, Proteolysis, SPTB, SPTBN1, SPTBN2, SPTAN1, Alzheimer’s, SCA5, Parkinson’s, Neurodegeneration, Proteostasis, RTK signaling, Calcium signaling, HIPPO/YAP signaling

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