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Title: HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells

The RNA binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. In this study, we found that RNA binding–deficient TDP-43 (produced by neurodegeneration-causing mutations or posttranslational acetylation in its RNA recognition motifs) drove TDP-43 demixing into intranuclear liquid spherical shells with liquid cores. These droplets, which we named “anisosomes”, have shells that exhibit birefringence, thus indicating liquid crystal formation. Guided by mathematical modeling, we identified the primary components of the liquid core to be HSP70 family chaperones, whose adenosine triphosphate (ATP)–dependent activity maintained the liquidity of shells and cores. In vivo proteasome inhibition within neurons, to mimic aging-related reduction of proteasome activity, induced TDP-43–containing anisosomes. These structures converted to aggregates when ATP levels were reduced. Thus, acetylation, HSP70, and proteasome activities regulate TDP-43 phase separation and conversion into a gel or solid phase.

 
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Award ID(s):
1920374
NSF-PAR ID:
10212763
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  
Publisher / Repository:
American Association for the Advancement of Science (AAAS)
Date Published:
Journal Name:
Science
Volume:
371
Issue:
6529
ISSN:
0036-8075
Page Range / eLocation ID:
Article No. eabb4309
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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  2. Abstract

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    Age‐related dementia syndromes are often not related to a single pathophysiological process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid transactive response DNA‐binding protein 43 (TDP‐43) pathology (AD/TDP). Here, we investigated neuronal integrity and pathological burden of TDP‐43 and tau, along the well‐charted trisynaptic hippocampal circuit (dentate gyrus [DG], CA3, and CA1) in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non‐amnestic dementia due to TDP‐43 proteinopathy associated with frontotemporal lobar degeneration (FTLD‐TDP).

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