Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43

Abstract

We have investigated the extent and pattern of immunostaining for the TAR DNA-binding protein, TDP-43, in 37 patients with frontotemporal lobar degeneration with ubiquitin (UBQ) pathology (FTLD-U). We confirm that TDP-43 protein is a component of the UBQ immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII) and neurites of the cerebral cortex and hippocampus in FTLD-U. We further show that the same three histological patterns, previously identified by us according to the form, number and distribution of the UBQ-ir NCI, NII and neurites are equivalently present in TDP-43 immunohistochemistry. TDP-43 immunoreactive (TDP-43-ir) NCI with rounded, spicular or skein-type appearance were seen in motor neurones of the trigeminal or facial cranial nerve nuclei in one patient with frontotemporal dementia (FTD) and in the spinal cord in three patients with FTD + motor neurone disease (MND). In patients with MND alone, TDP-43-ir NCI are common in anterior horn cells of the spinal cord, and occasionally seen in neurones of the hypoglossus nucleus. We show that TDP-43-ir NCI are also present within neurones in the superior and inferior olives in FTLD-U, and in some patients with MND. Although TDP-43 is normally seen as a nuclear protein, nuclear TDP-ir was not observed in neurones of the cerebral cortex, brainstem and spinal cord in FTLD-U or MND when NCI were present. We conclude that the UBQ-ir lesions of FTLD and MND are defined by the presence of TDP-43, and that these disorders can be subsumed into a single disease entity under the umbrella of TDP-43 proteinopathy.

TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration

“…Therefore we performed double immunofluorescence to label both ubiquitin aggregates and TDP-43. We found that loss of nuclear TDP-43 staining was occasionally seen in neurons with ubiquitin positive inclusions, similar to what has been reported in human FTLD-U and ALS (20) (Fig. 2 E-G).…”

“…Cytoplasmic aggregates of TDP-43, together with loss of normal nuclear TDP-43 staining, are a common feature in vulnerable neurons in both FTLD-U and ALS (6,20). However, immunohistochemical analysis of Prp-TDP43 A315T mouse brains using multiple different antibodies to TDP-43 did not show obvious cytoplasmic aggregates or inclusions, despite the striking abnormalities seen with ubiquitin immunostaining shown above.…”

Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD

“…Nuclear depletion of TDP-43 in Grn-KO retinal neurons precedes neurodegeneration Loss of nuclear TDP-43 is commonly observed in postmortem brain tissue from patients with FTLD-TDP (Neumann et al, 2006;Davidson et al, 2007), including FTLD associated with GRN mutations (Fig. 2 A).…”

A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

“…FTLD-U [6,7]. Recently, the transactive response (TAR) DNA-binding protein 43 (TDP-43) was identified as the major disease protein in UBIs that accumulate in the central nervous system (CNS) of patients with FTLD-U as well as in patients with sporadic and familial ALS [8], but not in the majority of patients with familial ALS (FALS) due to SOD-1 gene mutations [8][9][10][11][12]. These data provided compelling evidence that FTLD-U and ALS represent a clinicopathological spectrum of the same neurodegenerative disorder, i.e.…”