An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62‐positive, TDP‐43‐negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline

Abstract

The transactive response DNA binding protein (TDP-43) proteinopathies describe a clinico-pathological spectrum of multi-system neurodegeneration that spans motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure MND/ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP-43 proteinopathies. All patients initially presented with weakness of limbs and respiratory muscles and had a family history of MND/ALS. None had clinically identified cognitive decline or dementia during life and they died between 11 and 32 months after symptom onset. Neuropathological investigation revealed lower motor neuron involvement with TDP-43-positive inclusions typical of MND/ALS. In contrast, the cerebral pathology was atypical, with abundant star-shaped p62-immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP-43-positive inclusions were sparse. This pattern was also seen in the cerebellum where p62-positive, TDP-43-negative inclusions were frequent in granular cells. Western blots of cortical lysates, in contrast to those of sporadic MND/ALS and FTLD-TDP, showed high p62 levels and low TDP-43 levels with no high molecular weight smearing. MND/ALS-associated SOD1, FUS and TARDBP gene mutations were excluded; however, further investigations revealed that all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9-linked MND/ALS and FTLD. We conclude that these chromosome 9-linked MND/ALS cases represent a pathological sub-group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

“…4). This evidence supports that the abnormal accumulation of TDP-43, p62, and ubiquitin seen in patients with ALS and FTD with C9orf72 expansions (21,(38)(39)(40) is not induced by a loss of C9orf72 function mRNA and supports that ASO-mediated C9orf72 reductions should be tolerated in an adult nervous system and may be safe to use in ALS and FTD.…”

“…Abnormal aggregations of TDP-43, p62, and ubiquitin have been extensively described in the neuropathology of ALS and FTD with C9orf72 expansion (21,(38)(39)(40). After 18 wk of ASOmediated depletion of C9orf72 RNA, examination of tissue sections revealed that TDP-43 remained mainly nuclear in spinal cord, hippocampus, and cortex (Fig.…”

“…Among these, ALS and FTD from repeat expansions in C9orf72 display a unique neuropathology signature, including aggregation of protein biomarkers, such as p62, that are deposited in cerebellar Purkinje and granule cells and in hippocampal neurons (38,39). To this specific signature, we now add the presence of nuclear RNA foci containing the hexanucleotide repeats transcribed from both sense and antisense strands.…”

Frontotemporal dementia due to C9ORF72 mutations

“…30 Consistent with our results, a recent study found mild to moderate p62 and TDP-43 staining in the thalamus of 4 C9ϩ carriers with MND. 31 Thalamic atrophy has been described in FTLD-TDP type A, 5,32 but not in type B, which is typically associated with FTD-MND. Although most FTD-MND cases show FTLD-TDP type B histology, an unexpected feature of C9ORF72 pathology is the frequency of FTLD-TDP type A.…”

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

“…30 TDP-43 inclusions are also prominent in cases linked to chromosome 9p 31 but HREM-specific pathology includes abundant cytoplasmic and intranuclear p62-positive inclusions in the hippocampus and cerebellum that are TDP-43-negative. 32,33 Precisely, how the HREM causes TDP-43 mislocalisation and neurodegeneration is not currently known. Evidence that the HREM reduces levels of C9ORF72 transcripts implicates a loss of function, however, probes detecting the HREM transcript identified RNA foci within the nuclei of neurons in the frontal cortex and spinal cord.…”