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Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis.

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.

journal_name

Neuropathol Appl Neurobiol

journal_title

Neuropathology and applied neurobiology

authors

Gregory JM,Elliott E,McDade K,Bak T,Pal S,Chandran S,Abrahams S,Smith C

doi

10.1111/nan.12575

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

255-263

issue

3

eissn

0305-1846

issn

1365-2990

journal_volume

46

pub_type

杂志文章

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