Clusterin protects neurons against intracellular proteotoxicity

Jenna Gregory, Daniel R. Whiten, Rebecca A. Brown, Teresa P. Barros, Janet R. Kumita, Justin J. Yerbury, Sandeep Satapathy, Karina McDade, Colin Smith, Leila M. Luheshi, Christopher M. Dobson* (Corresponding Author), Mark R. Wilson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)


It is now widely accepted in the field that the normally secreted chaperone clusterin is redirected to the cytosol during endoplasmic reticulum (ER) stress, although the physiological function(s) of this physical relocation remain unknown. We have examined in this study whether or not increased expression of clusterin is able to protect neuronal cells against intracellular protein aggregation and cytotoxicity, characteristics that are strongly implicated in a range of neurodegenerative diseases. We used the amyotrophic lateral sclerosis-associated protein TDP-43 as a primary model to investigate the effects of clusterin on protein aggregation and neurotoxicity in complementary in vitro, neuronal cell and Drosophila systems. We have shown that clusterin directly interacts with TDP-43 in vitro and potently inhibits its aggregation, and observed that in ER stressed neuronal cells, clusterin co-localized with TDP-43 and specifically reduced the numbers of cytoplasmic inclusions. We further showed that the expression of TDP-43 in transgenic Drosophila neurons induced ER stress and that co-expression of clusterin resulted in a dramatic clearance of mislocalized TDP-43 from motor neuron axons, partially rescued locomotor activity and significantly extended lifespan. We also showed that in Drosophila photoreceptor cells, clusterin co-expression gave ER stress-dependent protection against proteotoxicity arising from both Huntingtin-Q128 and mutant (R406W) human tau. We therefore conclude that increased expression of clusterin can provide an important defense against intracellular proteotoxicity under conditions that mimic specific features of neurodegenerative disease.
Original languageEnglish
Article number81
JournalActa Neuropathologica Communications
Issue number81
Publication statusPublished - 7 Nov 2017

Bibliographical note

This work was supported by a Wellcome Trust/MRC strategic award (LML, TMP and CMD), the International Journal of Experimental Pathology (JG), the James Baird fund (JG), the BBSRC (CMD, LML, JRK), Grants-In-Aid from the Motor Neurone Disease Research Institute of Australia (GIA1223 & GIA1335) (MRW, JJY), an Illawarra Health and Medical Research Institute Dementia Research Grant (MRW), a Lloyd Binet PhD Scholarship (Australian Rotary Health) (RAB) and an Australian Government Postgraduate Award (DRW). The authors declare that there are no conflicts of interest.


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