Abstract
Aims
Clusterin is a topologically dynamic chaperone protein with the ability to participate in both intra- and extacellular proteostasis. Clusterin has been shown to be upregulated in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) and has been shown to protect against TDP-43 protein misfolding in animal and cell models. Previous studies have demonstrated an association between the pathological burden of TDP-43 misfolding and cognitive deficits in ALS, demonstrating high specificity, but correspondingly low sensitivity owing to a subset of individuals with no evidence of cognitive deficits despite a high burden of TDP-43 pathology, called mismatch cases.
Methods
Hypothesizing that differences in the ability to cope with protein misfolding in these cases may be due to differences in expression of protective mechanisms such as clusterin expression, we assessed the spatial expression of clusterin and another chaperone protein, HspB8, in post mortem brain tissue of mismatch cases. We employed a modified in situ hybridization technique called BaseScope, with single cell, single transcript resolution.
Results
Mismatch cases demonstrated differential spatial expression of clusterin, with a predominantly neuronal pattern, compared to cases with cognitive manifestations of their TDP-43 pathology who demonstrated a predominantly glial distribution of expression.
Conclusions
Our data suggest that, in individuals with TDP-43 pathology, predominantly neuronal expression of clusterin in extra-motor brain regions may indicate a cell protective mechanism delaying clinical manifestations such as cognitive dysfunction.
Clusterin is a topologically dynamic chaperone protein with the ability to participate in both intra- and extacellular proteostasis. Clusterin has been shown to be upregulated in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) and has been shown to protect against TDP-43 protein misfolding in animal and cell models. Previous studies have demonstrated an association between the pathological burden of TDP-43 misfolding and cognitive deficits in ALS, demonstrating high specificity, but correspondingly low sensitivity owing to a subset of individuals with no evidence of cognitive deficits despite a high burden of TDP-43 pathology, called mismatch cases.
Methods
Hypothesizing that differences in the ability to cope with protein misfolding in these cases may be due to differences in expression of protective mechanisms such as clusterin expression, we assessed the spatial expression of clusterin and another chaperone protein, HspB8, in post mortem brain tissue of mismatch cases. We employed a modified in situ hybridization technique called BaseScope, with single cell, single transcript resolution.
Results
Mismatch cases demonstrated differential spatial expression of clusterin, with a predominantly neuronal pattern, compared to cases with cognitive manifestations of their TDP-43 pathology who demonstrated a predominantly glial distribution of expression.
Conclusions
Our data suggest that, in individuals with TDP-43 pathology, predominantly neuronal expression of clusterin in extra-motor brain regions may indicate a cell protective mechanism delaying clinical manifestations such as cognitive dysfunction.
| Original language | English |
|---|---|
| Article number | 12575 |
| Pages (from-to) | 255–263 |
| Number of pages | 9 |
| Journal | Neuropathology and Applied Neurobiology |
| Volume | 46 |
| Issue number | 3 |
| Early online date | 28 Aug 2019 |
| DOIs | |
| Publication status | Published - 18 May 2020 |
Bibliographical note
The Editors of Neuropathology and Applied Neurobiology are committed to peer-review integrity and upholding the highest standards of review. As such, this article was peer-reviewed by independent, anonymous expert referees, and the authors (including CS) had no role in either the editorial decision or the handling of the paper. The authors thank (i) the MRC Edinburgh Brain Bank for supplying all post mortem brain material and the Scottish MND Register/CARE-MND Consortium for all clinical and demographic data. (ii) The Scottish MND Clinical Specialist, team in discussing and obtaining consent from MND patients for inclusion in these resources. (iii) MND Scotland and the Sylvia Aitken Charitable Trust for funding SA and CS to help to establish the MND Tissue bank. (iv) the Motor Neurone Disease Association and the Amyotrophic Lateral Sclerosis Association for funding the development and collection of ECAS data in the ALS patients and v) Steven Meldrum, Chris Crockford, Ratko Radakovic, Elaine Niven, Judy Newton, Gill Stott, and Jill Dunbar for their help with collection of the cognitive data. Funding: JMG is funded by a starter grant for clinical lecturers from the AMS (210JMG 3102 R45620), brain bank funding from the MRC (MR/L016400/1).Keywords
- ALS
- cognition
- ECAS
- Neuropathology
- TDP-43