{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nBeta‐III spectrin, encoded by SPTBN2, is a critical cytoskeletal protein that is most highly expressed in cerebellar Purkinje cells where it organizes the membrane skeleton by stabilizing key membrane proteins such as the glutamate transporter EAAT4 and the metabotropic glutamate receptor mGluR1. Early genetic investigations into the spectrum of autosomal dominant cerebellar ataxias have established that both dominant and recessive mutations in SPTBN2—ranging from in‐frame deletions and missense substitutions to truncating mutations—disrupt Purkinje cell function. Such genetic alterations compromise the normal trafficking and stabilization of membrane proteins, resulting in progressive ataxia, motor deficits, and, in some cases, cognitive impairment due to defective glutamatergic neurotransmission."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and biochemical analyses have provided considerable insight into how SPTBN2 normally functions at the molecular level. Investigation of its actin‐binding domain (ABD) has revealed that pathogenic variants—such as the L253P mutation—disrupt the autoinhibitory conformation of the tandem calponin homology domains, leading to an abnormally high affinity for F‐actin and reduced thermal stability. Such alterations in the dynamics of spectrin–actin interactions disturb the integrity of the cytoskeletal network, contributing to impaired synaptic plasticity and diminished neuronal output."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its essential role in neuronal cells, emerging evidence indicates that SPTBN2 also plays multifaceted roles in non‐neuronal tissues. Aberrant expression of SPTBN2 has been identified as a potential diagnostic biomarker in aspirin‐exacerbated respiratory disease, while its upregulation has been observed in malignancies such as papillary thyroid and colorectal cancers. Furthermore, in the context of non–small cell lung cancer, SPTBN2 interacts via its calponin homology domain with SLC7A11, facilitating the transporter’s membrane localization and thereby modulating ferroptosis and chemoresistance. These diverse functions underscore the importance of SPTBN2 in maintaining cytoskeletal integrity, regulating membrane protein trafficking, and influencing critical cellular signaling pathways in both neural and peripheral contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alfredo Brusco, Cinzia Gellera, Claudia Cagnoli, et al. 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