Hereditary dentatorubral-pallidoluysian atrophy: ubiquitinated filamentous inclusions in the cerebellar dentate nucleus neurons

Abstract

We examined the cerebellar dentate nucleus (CDN) in 16 patients with hereditary dentatorubral-pallidoluysian atrophy (DRPLA), one of the neurodegenerative diseases caused by expansion of a CAG repeat encoding a polyglutamine tract in the disease protein. In all patients, some CDN neurons were found to contain ubiquitinated filamentous inclusions in their cytoplasm. On hematoxylin and eosin preparations, these filamentous inclusions were eosinophilic, basophilic or amphophilic, and were often found in areas of pale cytoplasm. Electron microscopy revealed that they consisted of bundles of filaments that were somewhat thicker than neurofilaments. These features of the present inclusions were indistinguishable from those of skein-like inclusions (SLI) previously described in the lower motor neurons in sporadic amyotrophic lateral sclerosis. We conclude that SLI can also occur in the CDN in DRPLA and believe that they reflect a characteristic pathological process in this disease.

Rapidly progressive sporadic dentatorubral pallidoluysian atrophy with intracytoplasmic inclusions and no CAG repeat expansion

“…Intracytoplasmic inclusions have been previously reported by a Japanese group9 in a cohort of 10 pathology‐proven DRPLA subjects (presumably all familial type). In that report, the inclusions were only present in the cerebellar dentate nucleus; not throughout the pons, striatum, thalamus, and subthalamic nucleus, as in our case.…”

Mutant androgen receptor accumulation in spinal and bulbar muscular atrophy scrotal skin: A pathogenic marker

“…Electron microscopic immunohistochemistry with the 1C2 antibody demonstrated granular dense and amorphous aggregates corresponding to diffuse nuclear staining in both spinal motor neurons and epithelial cells of scrotal skin (see Figs 1B, C). Filamentous structures such as those reported in Huntington's disease, 25 dentatorubal-pallidoluysian atrophy (DRPLA), 26 and Machado-Joseph disease 27 were not seen. No diffuse nuclear staining was seen in the control subjects.…”

Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview

“…The frequency of ALS is about 6 per 100,000 individuals [44, 45], and about 10% of ALS cases are genetically related [46]. …”

“…ATN1 is the only gene known to be coupled with DRPLA. Discovery of pathogenic mutations in ATN1 has led to the identification of neuronal intra-nuclear inclusions in the brains of individuals with DRPLA [44, 45]. Accumulation of mutant ATN1 in neuronal nuclei is the most prominent neuropathological finding and is detected as diffused nuclear staining by antibody specifically detecting expanded polyglutamine stretches.…”