TDP-43: A reliable immunohistochemistry marker for inclusion body myositis?

Abstract

TDP-43 is a 414 amino acid protein encoded by the transactive response (TAR) DNA binding protein gene on chromosome 1p36. It was first cloned as a human protein capable of binding to the TAR DNA of HIV-1.11 It was later identified as part of a complex involved in splicing of the cystic fibrosis transmembrane conductance regulator gene.3 TDP-43 is highly conserved, ubiquitously expressed and predominantly localized to the nucleus under normal conditions. It consists of two RNA recognition motifs and a glycine-rich C-terminal region which interacts with other members of the heterogeneous ribonucleoprotein (hnRNP) family.2,5 TDP-43 is chiefly involved in well characterized transcription function and RNA splicing regulation. Recent studies suggest that TDP-43 may be involved in other cellular processes, such as microRNA biogenesis, apoptosis, cell division, mRNA stabilization and regulation of neuronal plasticity.2,5 Since its link to sporadic amyotrophic lateral sclerosis (sALS), frontotemporal dementia (FTD) with ubiquitinated protein inclusions (UBIs) (FTD-U) and FTD-U/ALS in 2006, overexpression of TDP-43 has been reported in other conditions with cellular overexpression, including Guaminian ALS-parkinsonism-dementia complex, progranulin gene mutation, VCP (Valosin-containing protein) gene mutation, dementia linked to chromosome 9 without VCP gene mutation, sporadic and hereditary IBM, and myofibrillar and desmin myopathies.6,7,9,12,14,15 Earlier this year, two independent researchers8,16 reported that mutations in the gene for another DNA/RNA binding protein, fused in sarcoma or translocation in liposarcoma (FUS/TLS), also trigger UBIs and premature degeneration of motor neurons. FUS/TLS protein has not yet been studied in IBM. Nevertheless, alteration in RNA processing and protein aggregates appears to be the key event in these motor neuron and muscle diseases. Sporadic inclusion body myositis (sIBM) is a common form of inflammatory muscle disease in older patients. In the first detailed pathological report of sIBM,4 Carpenter et al. commented on the characteristic inclusions as well as the nuclear degenerative process. Subsequent investigations (reviewed by Oldfors and Lindberg10) revealed similar inclusions – UBIs in both dominant and recessive forms of hereditary IBM (hIBM), oculopharyngeal muscular dystrophy, and in IBM with Paget disease of bone and frontotemporal dementia. Interestingly, when protein epitopes of UBIs in muscle fibers of sIBM were further investigated, it became clear that several “alien” molecules were overexpressed. These included -amyloid, phosphorylated tau and SMI-31 that incidentally were also the constituents of UBIs in the neurons of Alzheimer disease brains. These observations prompted Banwell and Engel1 to search for other protein molecules that were overexpressed in astrocytes and astroglial cells in the vicinity of senile plaques of Alzheimer disease brains. One such molecule Bcrystallin, indeed, was found to be overexpressed in sIBM.1 The demonstration of either immunoreactivity with antibodies to ubiquitin, SMI-31 or B-crystallin, or the finding of Congo red fluorescence ( -amyloid) then became the standard procedures for the histological diagnosis of IBM. Over the past year, TDP-43 immunoreactive UBIs have been reported in sIBM7,15 and in familial myopathies with or without vacuolar change.7,12,15 In this issue of Muscle and Nerve, Salajegheh and colleagues13 confirm and extend the recent observations7,12,15 of excessive TDP-43 in IBM muscle fibers. These findings are important on several counts. First, the authors found an average of nearly 1 in 4 Correspondence to: Rup Tandan, e-mail: rup.tandan@uvm.edu