Original Paper

Acta Neuropathologica

, Volume 113, Issue 5, pp 521-533

First online:

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

  • Yvonne DavidsonAffiliated withClinical Neuroscience Research Group, Division of Medicine and Neuroscience, Greater Manchester Neurosciences Centre, Hope Hospital, University of Manchester
  • , Thomas KelleyAffiliated withClinical Neuroscience Research Group, Division of Medicine and Neuroscience, Greater Manchester Neurosciences Centre, Hope Hospital, University of Manchester
  • , Ian R. A. MackenzieAffiliated withDepartment of Pathology, Vancouver General Hospital
  • , Stuart Pickering-BrownAffiliated withClinical Neuroscience Research Group, Division of Medicine and Neuroscience, Greater Manchester Neurosciences Centre, Hope Hospital, University of ManchesterDivision of Regenerative Medicine, University of Manchester
  • , Daniel Du PlessisAffiliated withClinical Neuroscience Research Group, Division of Medicine and Neuroscience, Greater Manchester Neurosciences Centre, Hope Hospital, University of Manchester
  • , David NearyAffiliated withClinical Neuroscience Research Group, Division of Medicine and Neuroscience, Greater Manchester Neurosciences Centre, Hope Hospital, University of Manchester
  • , Julie S. SnowdenAffiliated withClinical Neuroscience Research Group, Division of Medicine and Neuroscience, Greater Manchester Neurosciences Centre, Hope Hospital, University of Manchester
  • , David M. A. MannAffiliated withClinical Neuroscience Research Group, Division of Medicine and Neuroscience, Greater Manchester Neurosciences Centre, Hope Hospital, University of Manchester Email author 

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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.