An autopsied case of sporadic adult-onset amyotrophic lateral sclerosis with FUS-positive basophilic inclusions

Abstract

Basophilic inclusions (BIs), which are characterized by their staining properties of being weakly argyrophilic, reactive with Nissl staining, and immunohistochemically negative for tau and transactive response (TAR) DNA-binding protein 43 (TDP-43), have been identified in patients with juvenile-onset amyotrophic lateral sclerosis (ALS) and adult-onset atypical ALS with ophthalmoplegia, autonomic dysfunction, cerebellar ataxia, or a frontal lobe syndrome. Mutations in the fused in sarcoma gene (FUS) have been reported in cases of familial and sporadic ALS, and FUS immunoreactivity has been demonstrated in basophilic inclusion body disease (BIBD), neuronal intermediate filament inclusion disease (NIFID), and atypical frontotemporal lobar degeneration with ubiquitin-positive and tau-negative inclusions (aFTLD-U). In the present study, we immunohistochemically and ultrastructurally studied an autopsy case of sporadic adult-onset ALS with numerous BIs. The patient presented with the classical clinical course of ALS since 75 years of age and died at age 79. Postmortem examination revealed that both Betz cells in the motor cortex and motor neurons in the spinal cord were affected. The substantia nigra was spared. Notably, BIs were frequently observed in the motor neurons of the anterior horns, the inferior olivary nuclei, and the basal nuclei of Meynert. BIs were immunopositive for p62, LC3, and FUS, but immunonegative for tau, TDP-43, and neurofilament. Ultrastructurally, BIs consisted of filamentous or granular structures associated with degenerated organelles with no limiting membrane. There were no Bunina bodies, skein-like inclusions, or Lewy-like inclusions. All exons and exon/intron boundaries of the FUS gene were sequenced but no mutations were identified.

Widespread Microstructural White Matter Involvement in Amyotrophic Lateral Sclerosis: A Whole-Brain DTI Study

“…29,33 If we take these results together, our data support the hypothesis of an active and at least partially independent bilateral cortical process of degeneration with secondary damage to the CC, particularly in its midbody, known to be significantly involved in the process of axonal degeneration in ALS 34 and substantially formed by interhemispheric fibers connecting the motor cortices, as also demonstrated by diffusion tensor tractography. 35 According to previous neuropathologic findings, 27,34,36 ALS degenerative changes in the cerebral cortex mainly involve motor areas, though recent whole-brain voxel-based morphometry analyses have largely reported GM abnormalities even in extramotor regions. 12,14,15,20,31,37 Thereby, the trends of MD and RD changes, which largely overlapped in our patients in both the genu and splenium of the CC, may represent an increase in the extracellular volume secondary to axonal loss associated with injury to the myelin sheaths, as previously reported in human and animal models of demyelination and axonal degeneration.…”

Poly-A Binding Protein-1 Localization to a Subset of TDP-43 Inclusions in Amyotrophic Lateral Sclerosis Occurs More Frequently in Patients Harboring an Expansion inC9orf72

“…Another example of pathological inclusions found in ALS and FTD are basophilic inclusions. Basophilic inclusions are negative for TDP-43, but are positive for FUS and a number of other RNA binding proteins (3-5, 9, 16-19). TDP-43 and FUS are proteins involved in a range of RNA biogenesis processes, including the transport of RNA transcripts into cytoplasmic stress granules (20, 21).…”

Making Connections: Pathology and Genetics Link Amyotrophic Lateral Sclerosis with Frontotemporal Lobe Dementia

“…Recently, a single case has been described in the literature with adult-onset FUS mutation-negative SALS with FUS-immunoreactive basophilic inclusions (Matsuoka et al 2011). In this case, the inclusions were immunopositive for p62, LC3, and FUS, but immunonegative for tau, TDP-43, and neurofilament (Matsuoka et al 2011).…”

“…Histopathological analyses in these studies have shown these inclusions to be immunoreactive for FUS, p62, and ubiquitin but negative for TDP-43, hyperphosphorylated tau, α-synuclein, α-1-internexin, and neurofilament (Baumer et al 2010;Huang et al 2010;Suzuki et al 2010). Recently, a single case has been described in the literature with adult-onset FUS mutation-negative SALS with FUS-immunoreactive basophilic inclusions (Matsuoka et al 2011). In this case, the inclusions were immunopositive for p62, LC3, and FUS, but immunonegative for tau, TDP-43, and neurofilament (Matsuoka et al 2011).…”