In sporadic inclusion body myositis muscle fibres TDP‐43‐positive inclusions are less frequent and robust than p62 inclusions, and are not associated with paired helical filaments

Transactive response DNA-binding protein 43 (TDP-43) is a predominantly nuclear RNA/DNA-binding protein, also present in the cytoplasm (reviewed in [1,2]). Its functions are not fully understood, but it was reported to be involved in RNA processing, transcription and exon skipping [1,2]. Recent interest in TDP-43 was provoked by (i) discovering TDP-43-immunoreactive inclusions in the most common subtype of cerebral frontotemporal lobar degeneration (FTLD) associated with ubiquitin-positive inclusions, and in sporadic amyotrophic lateral sclerosis (ALS) [1,2]; and (ii) identification of mainly missense mutations of TDP-43 in familial and sporadic ALS [1,2]. In SOD1-mutant genetic ALS, TDP-43-immunoreactive inclusions are not present [2]. Although it was initially suggested that all ubiquitin-positive, tau-negative FTLD brains contain TDP-43-immunoreactive inclusions, subsequently some ubiquitin-positive, but TDP-43-negative, FTLD cases were identified [3,4]. Among other neurodegenerative diseases, TDP-43-immunoreactive inclusions were also demonstrated in brains of: 20–50% of sporadic Alzheimer disease (AD) brains [5,6], about 14% of familial AD and of Down syndrome, and in Lewy body disease [6,7]. In AD brain TDP-43-immunoreactive inclusions are usually considered secondary pathology [2]; in most cases they were immunonegative for phosphorylated tau and not associated with neurofibrillary tangles (NFTs) [5–8]. Also in contrast to FTLD-TDP brains, which contain a low molecular weight, 25 kDa TDP-43 cleaved fragment, which has been considered pathogenic and linked to TDP-43 cytotoxicity [1,9], AD brains do not contain this fragment [10]. p62, also known as sequestosome-1 (SQSTM1), is a ubiquitin-binding protein that is a common component of ubiquitinated multiprotein inclusions in protein aggregation disorders of the central nervous system, including AD and FTLD [11–13]. p62 is considered an integral component of NFTs in AD brain. In NFTs, p62 co-localizes with phosphorylated tau and is considered to participate in tau phosphorylation [12,14]. Because of the prominent presence of p62 in brains of patients with various neurological disorders, p62 immunostaining was recommended for neuropathological diagnosis [13]. Sporadic inclusion body myositis (s-IBM) is the most common muscle disease of persons age 50 years [15,16]. Characteristics of the s-IBM muscle biopsy are mononuclear cell inflammation and muscle fibres containing autophagic vacuoles (reviewed in 15–17). s-IBM abnormal muscle fibres, vacuolated and nonvacuolated, have accumulated ubiquitin-positive multiprotein aggregates containing misfolded proteins in the b-pleated sheet conformation of congophilic amyloid [15–17]. Intriguingly, s-IBM muscle fibres have several phenotypic similarities with brain tissue of AD and Parkinson disease Lewy bodies. These include accumulated aggregated amyloid-b (Ab), phosphorylated tau (p-tau) in the form of paired helical filaments (PHFs), which form intramuscle fibre bundles very similar to AD intraneuronal PHFs, accumulated a-synuclein and several other proteins (recently reviewed in 15,16). Inclusions immunoreactive for p62 were prominently accumulated in muscle fibres of all s-IBM muscle biopsies studied – consequently immunostaining for p62 was proposed as a pathological diagnostic marker for s-IBM [18]. In s-IBM muscle biopsies, most of the p62-immunopositive inclusions were linear or squiggly, and all co-localized with p-tau by light microscopy [18]. By immunoelectronmicroscopy, in s-IBM both p62 and p-tau were specifically associated with PHFs [18]. p62 was not immunoreactive in muscle fibre nuclei or in nuclei of inflammatory or connective tissue cells. In s-IBM muscle fibres p62 was significantly increased both on the protein and mRNA levels [18]. Transactive response DNA-binding protein 43immunoreactive cytoplasmic inclusions within s-IBM muscle fibres were first reported by Weihl et al. [19] and