Accumulation of phosphorylated TDP‐43 in the CNS of a patient with Cockayne syndrome

Abstract

Here, we report a case of Cockayne syndrome (CS) in a Japanese man who displayed a unique pathology of phosphorylated trans-activation response (TAR) DNA-binding protein 43 (pTDP-43) with abundant Rosenthal fibers. Many round pTDP-43-positive structures were detected throughout the CNS; however, most of them were located in two regions that also exhibited neuronal depletion: the cerebellar cortex and the inferior olivary nucleus. To a lesser extent, these aggregates were also present in the cerebellar white matter, around the subependymal regions in the brain stem, and in the spinal cord. Intraneuronal pTDP-43 inclusions were only observed in a small number of neurons in the inferior olivary nucleus. Double-label immunofluorescence revealed that many of the aggregates were localized to astrocytes. The observed distribution and the morphology of the pTDP-43-positive structures were unique and have not yet been reported. Therefore, a pTDP-43-related pathology may be implicated in CS as well as in other neurodegenerative diseases such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Whether the pathology of these diseases reflects a primary neurodegenerative process or a secondary reaction is not known.