Dystonin

Dystonin (DST) is a large cytoskeletal linker protein that integrates intermediate filaments, actin, and microtubule networks (UniProt: Q03001). It anchors keratin-containing intermediate filaments to hemidesmosomes in epithelial cells and regulates microtubule organization in sensory neurons to support axonal transport, including retrograde transport via dynein/dynactin interactions. The protein also regulates keratinocyte polarity and bundles actin filaments around the nucleus.

Dystonin is primarily associated with epithelial integrity and neuronal function. Pathogenic variants cause hereditary sensory and autonomic neuropathy type 6 (HSAN6), characterized by progressive degeneration of dorsal root and autonomic neurons, and epidermolysis bullosa simplex type 3, reflecting its essential roles in hemidesmosomal assembly and sensory neuron stability (UniProt: Q03001).

In Alzheimer's disease, dystonin shows ambiguous direction of change across brain fractions, with a mean log2 fold-change of −0.23 in post-mortem AD brain relative to age-matched controls (Chaparral AD proteomics). This modest, heterogeneous effect across the four measured subcellular fractions suggests dystonin's involvement may be compartment-dependent rather than uniformly altered in AD pathology.