• Neuroscience · Aug 2020

    Enhanced hyaluronan signaling and autophagy dysfunction by VPS35 D620N.

    • Abir A Rahman, Alejandro Soto-Avellaneda, Hyun Yong Jin, Iva Stojkovska, Nathan K Lai, Joshua E Albright, Abby R Webb, Emily Oe, Jacob P Valarde, Alexandra E Oxford, Paige E Urquhart, Brandon Wagner, Connor Brown, Isabella Amado, Peyton Vasquez, Nicholas Lehning, Veselin Grozdanov, Xinzhu Pu, Karin M Danzer, and Brad E Morrison.
    • Department of Biological Sciences, Boise State University, Boise, ID 83725, USA; Biomolecular Ph.D. Program, Boise State University, Boise, ID 83725, USA.
    • Neuroscience. 2020 Aug 10; 441: 33-45.

    AbstractThe motor features of Parkinson's disease (PD) result from the loss of dopaminergic (DA) neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. A PD-causing familial mutation in VPS35 (D620N) has been reported to inhibit autophagy. In order to identify signaling pathways responsible for this autophagy defect, we performed an unbiased screen using RNA sequencing (RNA-Seq) of wild-type or VPS35 D620N-expressing retinoic acid-differentiated SH-SY5Y cells. We report that VPS35 D620N-expressing cells exhibit transcriptome changes indicative of alterations in extracellular matrix (ECM)-receptor interaction as well as PI3K-AKT signaling, a pathway known to regulate autophagy. Hyaluronan (HA) is a major component of brain ECM and signals via the ECM receptors CD44, a top RNA-Seq hit, and HA-mediated motility receptor (HMMR) to the autophagy-regulating PI3K-AKT pathway. We find that high (>950 kDa), but not low (15-40 kDa), molecular weight HA treatment inhibits autophagy. In addition, VPS35 D620N facilitated enhanced HA-AKT signaling. Transcriptomic assessment and validation of protein levels identified the differential expression of CD44 and HMMR isoforms in VPS35 D620N mutant cells. We report that knockdown of HMMR or CD44 results in upregulated autophagy in cells expressing wild-type VPS35. However, only HMMR knockdown resulted in rescue of autophagy dysfunction by VPS35 D620N indicating a potential pathogenic role for this receptor and HA signaling in Parkinson's disease.Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

      Pubmed     Free full text   Copy Citation     Plaintext  

      Add institutional full text...

    Notes

     
    Knowledge, pearl, summary or comment to share?
    300 characters remaining
    help        
    You can also include formatting, links, images and footnotes in your notes
    • Simple formatting can be added to notes, such as *italics*, _underline_ or **bold**.
    • Superscript can be denoted by <sup>text</sup> and subscript <sub>text</sub>.
    • Numbered or bulleted lists can be created using either numbered lines 1. 2. 3., hyphens - or asterisks *.
    • Links can be included with: [my link to pubmed](http://pubmed.com)
    • Images can be included with: ![alt text](https://bestmedicaljournal.com/study_graph.jpg "Image Title Text")
    • For footnotes use [^1](This is a footnote.) inline.
    • Or use an inline reference [^1] to refer to a longer footnote elseweher in the document [^1]: This is a long footnote..

    hide…