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Lack of TAR-DNA binding protein-43 (TDP-43) pathology in human prion diseases.

Isaacs AM, Powell C, Webb TE, Linehan JM, Collinge J, Brandner S - Neuropathol. Appl. Neurobiol. (2008)

Bottom Line: Abnormal TDP-43 immunoreactivity has also been described in Alzheimer's disease, Lewy body diseases and Guam parkinsonism-dementia complex.Most PrP plaques contained ubiquitin, while synaptic PrP deposits were not associated with ubiquitin.These data do not support a role for TDP-43 in prion disease pathogenesis and argue that TDP-43 inclusions define a distinct group of neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: MRC Prion Unit, UCL Institute of Neurology, London, U.K.

ABSTRACT

Aims: TAR-DNA binding protein-43 (TDP-43) is the major ubiquitinated protein in the aggregates in frontotemporal dementia with ubiquitin-positive, tau-negative inclusions and motor neurone disease. Abnormal TDP-43 immunoreactivity has also been described in Alzheimer's disease, Lewy body diseases and Guam parkinsonism-dementia complex. We therefore aimed to determine whether there is TDP-43 pathology in human prion diseases, which are characterised by variable deposition of prion protein (PrP) aggregates in the brain as amyloid plaques or more diffuse deposits.

Material and methods: TDP-43, ubiquitin and PrP were analysed by immunohistochemistry and double-labelling immunofluorescence, in sporadic, acquired and inherited forms of human prion disease.

Results: Most PrP plaques contained ubiquitin, while synaptic PrP deposits were not associated with ubiquitin. No abnormal TDP-43 inclusions were identified in any type of prion disease case, and TDP-43 did not co-localize with ubiquitin-positive PrP plaques or with diffuse PrP aggregates.

Conclusions: These data do not support a role for TDP-43 in prion disease pathogenesis and argue that TDP-43 inclusions define a distinct group of neurodegenerative disorders.

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Related in: MedlinePlus

Prion protein (PrP), ubiquitin and TAR-DNA binding protein-43 (TDP-43) staining in sporadic and inherited prion diseases. (A–C) sCJD with synaptic PrP deposition, very little punctate ubiquitin deposits and normal TDP-43 labelling. (D,G,J,M) Inherited prion diseases with various types of prion protein deposits. (D–F) A117V mutation with diffuse, synaptic deposits, again with no marked ubiquitin deposition and no TDP-43 abnormalities. (G–I) GSS with P102L mutation shows marked ubiquitin aggregates in and around plaques. (J–L) Case of six-octapeptide-repeat insertion (144-bp insert) with abundant, dense prion protein deposits, mainly presenting with ‘primitive’ plaques (J), which are accompanied by ubiquitin aggregates (K), but no changes in TDP-43. (M–O) FFI with diffuse PrP plaques (M), no ubiquitin and no TDP-43 abnormalities. Numbers below the disease type indicate case numbers (see Table 1). Scale bar 100 µm for all images except C, I, F, L and O for which the scale bar is 50 µm.
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fig02: Prion protein (PrP), ubiquitin and TAR-DNA binding protein-43 (TDP-43) staining in sporadic and inherited prion diseases. (A–C) sCJD with synaptic PrP deposition, very little punctate ubiquitin deposits and normal TDP-43 labelling. (D,G,J,M) Inherited prion diseases with various types of prion protein deposits. (D–F) A117V mutation with diffuse, synaptic deposits, again with no marked ubiquitin deposition and no TDP-43 abnormalities. (G–I) GSS with P102L mutation shows marked ubiquitin aggregates in and around plaques. (J–L) Case of six-octapeptide-repeat insertion (144-bp insert) with abundant, dense prion protein deposits, mainly presenting with ‘primitive’ plaques (J), which are accompanied by ubiquitin aggregates (K), but no changes in TDP-43. (M–O) FFI with diffuse PrP plaques (M), no ubiquitin and no TDP-43 abnormalities. Numbers below the disease type indicate case numbers (see Table 1). Scale bar 100 µm for all images except C, I, F, L and O for which the scale bar is 50 µm.

Mentions: Disease-associated PrP was detected with the monoclonal antibody ICSM35 as described in the methods. We scored the abundance of PrP plaques and diffuse PrP aggregates for each case in a semi-quantitative assessment, and analysed ubiquitin pathology in these scored cases. As expected, vCJD brains contained abundant PrP-positive plaques (Figure 1A,D), as did one inherited prion disease case with a six-octapeptide-repeat insertion (6OPRI) in PRNP (Figure 2J). Interestingly, another case with the same 6OPRI insertion mutation had no PrP plaques, but rather fine axonal and dendritic PrP staining in grey and white matter, confirming the neuropathological heterogeneity even of cases with the same mutation (data not shown). The P102L (GSS) brain contained mature PrP plaques (Figure 2G), while the D178N (FFI) case had more diffuse or primitive plaques (but no core plaques) (Figure 2M). PrP plaques were consistently dotted with small ubiquitin aggregates, except in the D178N (FFI) case in which the correlation between the diffuse plaques and ubiquitin deposits was less obvious (Figure 2N). The plaques could be clearly identified by ubiquitin immunoreactivity using both standard IHC and IF (Figure 3). Double labelling confirmed the presence of small ubiquitin deposits within PrP plaques (Figure 3), and also showed that some D178N (FFI) plaques contained ubiquitin deposits (Figure 3F).


Lack of TAR-DNA binding protein-43 (TDP-43) pathology in human prion diseases.

Isaacs AM, Powell C, Webb TE, Linehan JM, Collinge J, Brandner S - Neuropathol. Appl. Neurobiol. (2008)

Prion protein (PrP), ubiquitin and TAR-DNA binding protein-43 (TDP-43) staining in sporadic and inherited prion diseases. (A–C) sCJD with synaptic PrP deposition, very little punctate ubiquitin deposits and normal TDP-43 labelling. (D,G,J,M) Inherited prion diseases with various types of prion protein deposits. (D–F) A117V mutation with diffuse, synaptic deposits, again with no marked ubiquitin deposition and no TDP-43 abnormalities. (G–I) GSS with P102L mutation shows marked ubiquitin aggregates in and around plaques. (J–L) Case of six-octapeptide-repeat insertion (144-bp insert) with abundant, dense prion protein deposits, mainly presenting with ‘primitive’ plaques (J), which are accompanied by ubiquitin aggregates (K), but no changes in TDP-43. (M–O) FFI with diffuse PrP plaques (M), no ubiquitin and no TDP-43 abnormalities. Numbers below the disease type indicate case numbers (see Table 1). Scale bar 100 µm for all images except C, I, F, L and O for which the scale bar is 50 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2607533&req=5

fig02: Prion protein (PrP), ubiquitin and TAR-DNA binding protein-43 (TDP-43) staining in sporadic and inherited prion diseases. (A–C) sCJD with synaptic PrP deposition, very little punctate ubiquitin deposits and normal TDP-43 labelling. (D,G,J,M) Inherited prion diseases with various types of prion protein deposits. (D–F) A117V mutation with diffuse, synaptic deposits, again with no marked ubiquitin deposition and no TDP-43 abnormalities. (G–I) GSS with P102L mutation shows marked ubiquitin aggregates in and around plaques. (J–L) Case of six-octapeptide-repeat insertion (144-bp insert) with abundant, dense prion protein deposits, mainly presenting with ‘primitive’ plaques (J), which are accompanied by ubiquitin aggregates (K), but no changes in TDP-43. (M–O) FFI with diffuse PrP plaques (M), no ubiquitin and no TDP-43 abnormalities. Numbers below the disease type indicate case numbers (see Table 1). Scale bar 100 µm for all images except C, I, F, L and O for which the scale bar is 50 µm.
Mentions: Disease-associated PrP was detected with the monoclonal antibody ICSM35 as described in the methods. We scored the abundance of PrP plaques and diffuse PrP aggregates for each case in a semi-quantitative assessment, and analysed ubiquitin pathology in these scored cases. As expected, vCJD brains contained abundant PrP-positive plaques (Figure 1A,D), as did one inherited prion disease case with a six-octapeptide-repeat insertion (6OPRI) in PRNP (Figure 2J). Interestingly, another case with the same 6OPRI insertion mutation had no PrP plaques, but rather fine axonal and dendritic PrP staining in grey and white matter, confirming the neuropathological heterogeneity even of cases with the same mutation (data not shown). The P102L (GSS) brain contained mature PrP plaques (Figure 2G), while the D178N (FFI) case had more diffuse or primitive plaques (but no core plaques) (Figure 2M). PrP plaques were consistently dotted with small ubiquitin aggregates, except in the D178N (FFI) case in which the correlation between the diffuse plaques and ubiquitin deposits was less obvious (Figure 2N). The plaques could be clearly identified by ubiquitin immunoreactivity using both standard IHC and IF (Figure 3). Double labelling confirmed the presence of small ubiquitin deposits within PrP plaques (Figure 3), and also showed that some D178N (FFI) plaques contained ubiquitin deposits (Figure 3F).

Bottom Line: Abnormal TDP-43 immunoreactivity has also been described in Alzheimer's disease, Lewy body diseases and Guam parkinsonism-dementia complex.Most PrP plaques contained ubiquitin, while synaptic PrP deposits were not associated with ubiquitin.These data do not support a role for TDP-43 in prion disease pathogenesis and argue that TDP-43 inclusions define a distinct group of neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: MRC Prion Unit, UCL Institute of Neurology, London, U.K.

ABSTRACT

Aims: TAR-DNA binding protein-43 (TDP-43) is the major ubiquitinated protein in the aggregates in frontotemporal dementia with ubiquitin-positive, tau-negative inclusions and motor neurone disease. Abnormal TDP-43 immunoreactivity has also been described in Alzheimer's disease, Lewy body diseases and Guam parkinsonism-dementia complex. We therefore aimed to determine whether there is TDP-43 pathology in human prion diseases, which are characterised by variable deposition of prion protein (PrP) aggregates in the brain as amyloid plaques or more diffuse deposits.

Material and methods: TDP-43, ubiquitin and PrP were analysed by immunohistochemistry and double-labelling immunofluorescence, in sporadic, acquired and inherited forms of human prion disease.

Results: Most PrP plaques contained ubiquitin, while synaptic PrP deposits were not associated with ubiquitin. No abnormal TDP-43 inclusions were identified in any type of prion disease case, and TDP-43 did not co-localize with ubiquitin-positive PrP plaques or with diffuse PrP aggregates.

Conclusions: These data do not support a role for TDP-43 in prion disease pathogenesis and argue that TDP-43 inclusions define a distinct group of neurodegenerative disorders.

Show MeSH
Related in: MedlinePlus