Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Article Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Team
    • Feedback
    • Reprints
    • Impact Factor
    • Editorial Fellowship Application Process
  • ASN Kidney News
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Article Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Team
    • Feedback
    • Reprints
    • Impact Factor
    • Editorial Fellowship Application Process
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
Basic Research
You have accessRestricted Access

Distinct Modes of Balancing Glomerular Cell Proteostasis in Mucolipidosis Type II and III Prevent Proteinuria

Wiebke Sachs, Marlies Sachs, Elke Krüger, Stephanie Zielinski, Oliver Kretz, Tobias B. Huber, Anke Baranowsky, Lena Marie Westermann, Renata Voltolini Velho, Nataniel Floriano Ludwig, Timur Alexander Yorgan, Giorgia Di Lorenzo, Katrin Kollmann, Thomas Braulke, Ida Vanessa Schwartz, Thorsten Schinke, Tatyana Danyukova, Sandra Pohl and Catherine Meyer-Schwesinger
JASN August 2020, 31 (8) 1796-1814; DOI: https://doi.org/10.1681/ASN.2019090960
Wiebke Sachs
1Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marlies Sachs
1Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elke Krüger
2Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephanie Zielinski
1Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Oliver Kretz
3III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tobias B. Huber
3III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anke Baranowsky
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lena Marie Westermann
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Renata Voltolini Velho
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nataniel Floriano Ludwig
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5Postgraduate Program in Genetics and Molecular Biology, Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timur Alexander Yorgan
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giorgia Di Lorenzo
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katrin Kollmann
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas Braulke
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ida Vanessa Schwartz
5Postgraduate Program in Genetics and Molecular Biology, Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thorsten Schinke
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tatyana Danyukova
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sandra Pohl
4Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Catherine Meyer-Schwesinger
1Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Visual Abstract

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Significance Statement

Patients with the severe lysosomal storage disorder mucolipidosis II (MLII) have mild microalbuminuria, among other symptoms, but patients with the milder MLIII do not have proteinuria. Both conditions result from mutations in the same gene. Mouse models of each disorder reveal that distinct mechanisms compensate for the disruption in protein synthesis balance in glomeruli. Both MLII and MLIII downregulate the protein complex mTORC1 (mammalian target of rapamycin complex 1) signaling to dampen protein synthesis, but MLII also increases the integrated stress response and MLIII activates the proteasome system.

Abstract

Background The mechanisms balancing proteostasis in glomerular cells are unknown. Mucolipidosis (ML) II and III are rare lysosomal storage disorders associated with mutations of the Golgi-resident GlcNAc-1-phosphotransferase, which generates mannose 6-phosphate residues on lysosomal enzymes. Without this modification, lysosomal enzymes are missorted to the extracellular space, which results in lysosomal dysfunction of many cell types. Patients with MLII present with severe skeletal abnormalities, multisystemic symptoms, and early death; the clinical course in MLIII is less progressive. Despite dysfunction of a major degradative pathway, renal and glomerular involvement is rarely reported, suggesting organ-specific compensatory mechanisms.

Methods MLII mice were generated and compared with an established MLIII model to investigate the balance of protein synthesis and degradation, which reflects glomerular integrity. Proteinuria was assessed in patients. High-resolution confocal microscopy and functional assays identified proteins to deduce compensatory modes of balancing proteostasis.

Results Patients with MLII but not MLIII exhibited microalbuminuria. MLII mice showed lysosomal enzyme missorting and several skeletal alterations, indicating that they are a useful model. In glomeruli, both MLII and MLIII mice exhibited reduced levels of lysosomal enzymes and enlarged lysosomes with abnormal storage material. Nevertheless, neither model had detectable morphologic or functional glomerular alterations. The models rebalance proteostasis in two ways: MLII mice downregulate protein translation and increase the integrated stress response, whereas MLIII mice upregulate the proteasome system in their glomeruli. Both MLII and MLIII downregulate the protein complex mTORC1 (mammalian target of rapamycin complex 1) signaling, which decreases protein synthesis.

Conclusions Severe lysosomal dysfunction leads to microalbuminuria in some patients with mucolipidosis. Mouse models indicate distinct compensatory pathways that balance proteostasis in MLII and MLIII.

  • mucolipidosis
  • osteopenia
  • proteotoxic stress
  • integrated stress response
  • glomerular disease
  • lysosomal storage disorder
  • Copyright © 2020 by the American Society of Nephrology
View Full Text

Log in using your username and password

Forgot your user name or password?

Log in through your institution

You may be able to gain access using your login credentials for your institution. Contact your library if you do not have a username and password.

Purchase access

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$27.00

You will have access to the article for 24 hours.  

If you do not have an account, you will need to create one and you will be asked for your name, email address and other information.  Just like commercial web sites, we do need details from you in order to complete your purchase of an article.  Select the "Create an Account" link to create your account. 

You will then be asked to register a user name, email address and you will need to create a password that is at least eight characters in length. As you move through the registration page, you will have to verify you are a person by completing a Captcha request.   Lastly, your first and last name will be required. 

Once your information is successfully saved, the system will redisplay the home page of the journal.  From there, navigate back to the article to purchase.  Select the article and at the bottom of the page, use the credentials you just created to login. The article will be added to your shopping cart.  You can continue to navigate across JASN and CJASN adding to your cart from both journals. When you are ready to complete your purchse, select the Shopping Cart from the upper right hand corner of the page and follow the onscreen instructions. 

PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 31 (8)
Journal of the American Society of Nephrology
Vol. 31, Issue 8
August 2020
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Distinct Modes of Balancing Glomerular Cell Proteostasis in Mucolipidosis Type II and III Prevent Proteinuria
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Distinct Modes of Balancing Glomerular Cell Proteostasis in Mucolipidosis Type II and III Prevent Proteinuria
Wiebke Sachs, Marlies Sachs, Elke Krüger, Stephanie Zielinski, Oliver Kretz, Tobias B. Huber, Anke Baranowsky, Lena Marie Westermann, Renata Voltolini Velho, Nataniel Floriano Ludwig, Timur Alexander Yorgan, Giorgia Di Lorenzo, Katrin Kollmann, Thomas Braulke, Ida Vanessa Schwartz, Thorsten Schinke, Tatyana Danyukova, Sandra Pohl, Catherine Meyer-Schwesinger
JASN Aug 2020, 31 (8) 1796-1814; DOI: 10.1681/ASN.2019090960

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Distinct Modes of Balancing Glomerular Cell Proteostasis in Mucolipidosis Type II and III Prevent Proteinuria
Wiebke Sachs, Marlies Sachs, Elke Krüger, Stephanie Zielinski, Oliver Kretz, Tobias B. Huber, Anke Baranowsky, Lena Marie Westermann, Renata Voltolini Velho, Nataniel Floriano Ludwig, Timur Alexander Yorgan, Giorgia Di Lorenzo, Katrin Kollmann, Thomas Braulke, Ida Vanessa Schwartz, Thorsten Schinke, Tatyana Danyukova, Sandra Pohl, Catherine Meyer-Schwesinger
JASN Aug 2020, 31 (8) 1796-1814; DOI: 10.1681/ASN.2019090960
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Visual Abstract
    • Abstract
    • Methods
    • Results
    • Discussion
    • Disclosures
    • Funding
    • Acknowledgments
    • Supplemental Material
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance
  • Urinary Single-Cell Profiling Captures the Cellular Diversity of the Kidney
  • Impairment of Proteasome Function in Podocytes Leads to CKD
Show more Basic Research

Cited By...

  • No citing articles found.
  • Google Scholar

Similar Articles

Related Articles

  • PubMed
  • Google Scholar

Keywords

  • mucolipidosis
  • osteopenia
  • proteotoxic stress
  • integrated stress response
  • glomerular disease
  • lysosomal storage disorder

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire