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AβPP-tau-HAS1 axis trigger HAS1-related nuclear speckles and gene transcription in Alzheimer's disease

Zhang, Ya Hong ; Sun, Xing Tong ; Guo, Rui Fang ; Feng, Gang Yi ; Gao, Hui Ling ; Zhong, Man Li ; Tian, Li Wen ; Qiu, Zhong Yi ; Cui, Yu Wei and Li, Jia Yi LU , et al. (2024) In Matrix Biology 129. p.29-43
Abstract

As the backbone of the extracellular matrix (ECM) and the perineuronal nets (PNNs), hyaluronic acid (HA) provides binding sites for proteoglycans and other ECM components. Although the pivotal of HA has been recognized in Alzheimer's disease (AD), few studies have addressed the relationship between AD pathology and HA synthases (HASs). Here, HASs in different regions of AD brains were screened in transcriptomic database and validated in AβPP/PS1 mice. We found that HAS1 was distributed along the axon and nucleus. Its transcripts were reduced in AD patients and AβPP/PS1 mice. Phosphorylated tau (p-tau) mediates AβPP-induced cytosolic-nuclear translocation of HAS1, and negatively regulated the stability, monoubiquitination, and... (More)

As the backbone of the extracellular matrix (ECM) and the perineuronal nets (PNNs), hyaluronic acid (HA) provides binding sites for proteoglycans and other ECM components. Although the pivotal of HA has been recognized in Alzheimer's disease (AD), few studies have addressed the relationship between AD pathology and HA synthases (HASs). Here, HASs in different regions of AD brains were screened in transcriptomic database and validated in AβPP/PS1 mice. We found that HAS1 was distributed along the axon and nucleus. Its transcripts were reduced in AD patients and AβPP/PS1 mice. Phosphorylated tau (p-tau) mediates AβPP-induced cytosolic-nuclear translocation of HAS1, and negatively regulated the stability, monoubiquitination, and oligomerization of HAS1, thus reduced the synthesis and release of HA. Furthermore, non-ubiquitinated HAS1 mutant lost its enzyme activity, and translocated from the cytosol into the nucleus, forming nuclear speckles (NS). Unlike the splicing-related NS, less than 1 % of the non-ubiquitinated HAS1 co-localized with SRRM2, proving the regulatory role of HAS1 in gene transcription, indirectly. Thus, differentially expressed genes (DEGs) related to both non-ubiquitinated HAS1 mutant and AD were screened using transcriptomic datasets. Thirty-nine DEGs were identified, with 64.1 % (25/39) showing consistent results in both datasets. Together, we unearthed an important function of the AβPP-p-tau-HAS1 axis in microenvironment remodeling and gene transcription during AD progression, involving the ubiquitin-proteasome, lysosome, and NS systems.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, Extracellular matrix, Hyaluronan synthases, Nuclear speckles, Phosphorylated tau, Ubiquitylation
in
Matrix Biology
volume
129
pages
15 pages
publisher
Elsevier
external identifiers
  • scopus:85189446280
  • pmid:38518923
ISSN
0945-053X
DOI
10.1016/j.matbio.2024.03.003
language
English
LU publication?
yes
id
f7ad97f1-7531-4690-b9c9-709ad391f393
date added to LUP
2024-04-24 14:28:39
date last changed
2024-06-19 19:37:10
@article{f7ad97f1-7531-4690-b9c9-709ad391f393,
  abstract     = {{<p>As the backbone of the extracellular matrix (ECM) and the perineuronal nets (PNNs), hyaluronic acid (HA) provides binding sites for proteoglycans and other ECM components. Although the pivotal of HA has been recognized in Alzheimer's disease (AD), few studies have addressed the relationship between AD pathology and HA synthases (HASs). Here, HASs in different regions of AD brains were screened in transcriptomic database and validated in AβPP/PS1 mice. We found that HAS1 was distributed along the axon and nucleus. Its transcripts were reduced in AD patients and AβPP/PS1 mice. Phosphorylated tau (p-tau) mediates AβPP-induced cytosolic-nuclear translocation of HAS1, and negatively regulated the stability, monoubiquitination, and oligomerization of HAS1, thus reduced the synthesis and release of HA. Furthermore, non-ubiquitinated HAS1 mutant lost its enzyme activity, and translocated from the cytosol into the nucleus, forming nuclear speckles (NS). Unlike the splicing-related NS, less than 1 % of the non-ubiquitinated HAS1 co-localized with SRRM2, proving the regulatory role of HAS1 in gene transcription, indirectly. Thus, differentially expressed genes (DEGs) related to both non-ubiquitinated HAS1 mutant and AD were screened using transcriptomic datasets. Thirty-nine DEGs were identified, with 64.1 % (25/39) showing consistent results in both datasets. Together, we unearthed an important function of the AβPP-p-tau-HAS1 axis in microenvironment remodeling and gene transcription during AD progression, involving the ubiquitin-proteasome, lysosome, and NS systems.</p>}},
  author       = {{Zhang, Ya Hong and Sun, Xing Tong and Guo, Rui Fang and Feng, Gang Yi and Gao, Hui Ling and Zhong, Man Li and Tian, Li Wen and Qiu, Zhong Yi and Cui, Yu Wei and Li, Jia Yi and Zhao, Pu}},
  issn         = {{0945-053X}},
  keywords     = {{Alzheimer's disease; Extracellular matrix; Hyaluronan synthases; Nuclear speckles; Phosphorylated tau; Ubiquitylation}},
  language     = {{eng}},
  pages        = {{29--43}},
  publisher    = {{Elsevier}},
  series       = {{Matrix Biology}},
  title        = {{AβPP-tau-HAS1 axis trigger HAS1-related nuclear speckles and gene transcription in Alzheimer's disease}},
  url          = {{http://dx.doi.org/10.1016/j.matbio.2024.03.003}},
  doi          = {{10.1016/j.matbio.2024.03.003}},
  volume       = {{129}},
  year         = {{2024}},
}