p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS

Abstract

Neuronal cytoplasmic inclusions (NCIs) containing phosphorylated TDP-43 (p-TDP-43) are the pathological hallmarks of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and FTLD-TDP. The vast majority of NCIs in the brain and spinal cord also label for ubiquitin and p62, however, we have previously reported a subset of TDP-43 proteinopathy patients who have unusual and abundant p62 positive, TDP-43 negative inclusions in the cerebellum and hippocampus. Here we sought to determine whether these cases carry the hexanucleotide repeat expansion in C9orf72. Repeat primer PCR was performed in 36 MND/ALS, FTLD-MND/ALS and FTLD-TDP cases and four controls. Fourteen individuals with the repeat expansion were detected. In all the 14 expansion mutation cases there were abundant globular and star-shaped p62 positive NCIs in the pyramidal cell layer of the hippocampus, the vast majority of which were p-TDP-43 negative. p62 positive NCIs were also abundant in the cerebellar granular and molecular layers in all cases and in Purkinje cells in 12/14 cases but they were only positive for p-TDP-43 in the granular layer of one case. Abundant p62 positive, p-TDP-43 negative neuronal intranuclear inclusions (NIIs) were seen in 12/14 cases in the pyramidal cell layer of the hippocampus and in 6/14 cases in the cerebellar granular layer. This unusual combination of inclusions appears pathognomonic for C9orf72 repeat expansion positive MND/ALS and FTLD-TDP which we believe form a pathologically distinct subset of TDP-43 proteinopathies. Our results suggest that proteins other than TDP-43 are binding p62 and aggregating in response to the mutation which may play a mechanistic role in neurodegeneration.

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

“…Positive cases were defined where p62‐positive, TDP‐43‐negative NCI within either the cerebellum (see [8]) or hippocampus (see [7]) could be clearly seen under low power objective (×20) and the majority of high power fields (×40) contained at least two NCI. Either negative cases were completely devoid of p62 immunostaining, or small amounts of apparently extracellular and ‘extraneous’ p62‐positive particulate material was observed in occasional high power fields.…”

“…Most of the early pathological descriptions following the discovery of the C9ORF72 mutation indicated that the associated TDP‐43 pathology was usually type B, characterized by NCI in all cortical layers but with relatively few dystrophic neurites or neuronal intranuclear inclusions [7, 8, 9, 15]. However, more recent studies have frequently reported a significant proportion of C9ORF72 mutation cases to have other patterns of FTLD‐TDP, most often type A [9, 11, 15], and rarely type C [16].…”

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.…”

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

“…conditions in which hippocampal pathology has been shown to play a role, such as in AD (Palop and Mucke, 2009), and C9orf72-related motor neuron disease and frontotemporal lobe dementia (Al-Sarraj et al, 2011;Cooper-Knock et al, 2012), as well as possibly chronic traumatic encephalopathy (CTE) (McKee et al, 2013).…”