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Lack of TAR-DNA binding protein-43 (TDP-43) pathology in human prion diseases
A M Isaacs1, C Powell, T E Webb
1MRC Prion Unit, UCL Institute of Neurology, London, U.K.
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.
Insights
TAR-DNA binding protein-43 (TDP-43) pathology was investigated in human prion diseases. No abnormal TDP-43 inclusions were found, suggesting TDP-43 does not play a role in prion disease.
Area of Science:
- Neurodegenerative diseases
- Proteinopathies
- Prion diseases
Background:
- TAR-DNA binding protein-43 (TDP-43) is implicated in frontotemporal dementia and motor neurone disease.
- Abnormal TDP-43 is found in Alzheimer's and Lewy body diseases.
- Prion diseases are characterized by prion protein (PrP) aggregates.
Purpose of the Study:
- To investigate TDP-43 pathology in human prion diseases.
- To determine if TDP-43 aggregates are present in prion disease brains.
- To assess the co-localization of TDP-43 with PrP deposits.
Main Methods:
- Immunohistochemistry and double-labeling immunofluorescence were used.
- TDP-43, ubiquitin, and PrP were analyzed.
- Sporadic, acquired, and inherited forms of human prion disease were examined.
Main Results:
- Most PrP plaques contained ubiquitin; synaptic PrP deposits did not.
- No abnormal TDP-43 inclusions were identified in any prion disease cases.
- TDP-43 did not co-localize with ubiquitin-positive PrP plaques or diffuse PrP aggregates.
Conclusions:
- These findings do not support a role for TDP-43 in prion disease pathogenesis.
- TDP-43 inclusions appear to define a distinct group of neurodegenerative disorders.
- Prion diseases and TDP-43 proteinopathies are pathologically separate.
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