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
Hypothesising 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 suggests 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 languageEnglish
JournalNeuropathology and Applied Neurobiology
Early online date28 Aug 2019
DOIs
Publication statusE-pub ahead of print - 28 Aug 2019

Keywords

  • ALS
  • cognition
  • ECAS
  • neuropatholofy
  • TDP-43

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