TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing.

Acta Neuropathol 2009 Sep 28;118(3):359-69. Epub 2009 Mar 28.

Clinical Neuroscience Research Group, Faculty of Medical and Human Sciences, Greater Manchester Neurosciences Centre, School of Translational Medicine, Hope Hospital, University of Manchester, Salford, M6 8HD, UK.

Ubiquitin immunoreactive (UBQ-ir) inclusions were present to variable extents in the inferior olivary nucleus (ION) in 37/48 (77%) patients with frontotemporal lobar degeneration (FTLD), in 10/11 (91%) patients with motor neurone disease (MND), in 5/5 (100%) patients with Alzheimer's disease (AD), 5/7 (71%) patients with dementia with Lewy bodies, 13/19 (68%) patients with Parkinson's disease, 11/11(100%) patients with Progressive Supranuclear Palsy, 2/6 (33%) patients with Multisystem Atrophy, 1/3 (33%) patients with Huntington's disease and in 14/14 (100%) normal elderly control subjects. In FTLD, UBQ-ir inclusions were present in 26/32 (81%) patients with FTLD-U, in 10/15 (67%) patients with tauopathy, and in the single patient with Dementia Lacking Distinctive Histology. In 13 FTLD-U patients, and in a single AD and in 2 MND patients, the UBQ-ir inclusions had a rounded, spicular or skein-type appearance, and these were also TDP-43 immunoreactive (TDP-43-ir). In all other affected patients in all diagnostic groups, and in control subjects, the UBQ-ir neuronal cytoplasmic inclusions (NCI) were of a conglomerated type, resembling a cluster of large granules or globules, but were never TDP-43-ir. In 3 of the 13 FTLD-U patients with spicular NCI, conglomerated NCI were also present but in separate cells. Double-labelling immunohistochemistry, and confocal microscopy, for UBQ and TDP-43 confirmed that only the spicular UBQ-ir inclusions in patients with FTLD-U, AD and MND contained TDP-43, though in these patients there were occasional TDP-43 immunoreactive inclusions that were not UBQ-ir. Nuclear TDP-43 immunoreactivity was absent in ION in FTLD-U, AD or MND when TDP-43 cytoplasmic inclusions were present, but remained in neurones with UBQ-ir, TDP-43 negative inclusions. The target protein within the UBQ-ir, TDP-43-negative inclusions remains unknown, but present studies indicate that this is not tau, neurofilament or internexin proteins. These TDP-43 negative, UBQ-ir inclusions appear to be more related to ageing than neurodegeneration, and are without apparent diagnostic significance. The pathophysiological mechanism leading to their formation, and any consequences their presence may have on nerve cell function, remain unknown.

Download full-text PDF

Source Listing
September 2009
16 Reads

Publication Analysis

Top Keywords

ubq-ir inclusions
cytoplasmic inclusions
lobar degeneration
33% patients
ftld-u patients
frontotemporal lobar
nci conglomerated
ftld-u mnd
tdp-43 immunoreactive
control subjects
patients ftld-u
tdp-43 negative
conglomerated type
groups control
diagnostic groups


(Supplied by CrossRef)

C Amador-Ortiz et al.
Ann Neurol 2007

T Arai et al.
Biochem Biophys Res Commun 2006

M Baker et al.
Nature 2006

H Barden et al.
J Neuropathol Exp Neurol 1970

BF Boeve et al.
Brain 2006

B Brooks et al.
Amyotroph Lateral Scler Other Motor Neuron Disord 2000

A Brun et al.
J Neurol Neurosurg Psychiatry 1994

NJ Cairns et al.
Acta Neuropathol 2007

M Cruts et al.
Nature 2006

Y Davidson et al.
Acta Neuropathol 2007

DW Dickson et al.
Acta Neuropathol 2007

Similar Publications