Abstract/Details

The ubiquitin E3 ligase Human Homolog of Drosophila Ariadne-1 (HHARI) is a structural and functional homolog of Parkin and is required for myogenesis


2008 2008

Other formats: Order a copy

Abstract (summary)

Several genes implicated in Parkinson's disease (PD) encode components of the ubiquitin-proteasome pathway. In a specific form of PD (human Autosomal Recessive Juvenile Parkinsonism, AR-JP), loss of functional Parkin (ubiquitin E3 ligase) results in a selective loss of midbrain dopaminergic neurons and a absence of Lewy bodies (LB) from the surviving dopaminergic neurons. Since cells in patients with AR-JP do not express functional Parkin, it is unclear why most neuronal and non-neuronal populations remain unaffected. One possible explanation is that most cells express a redundant ubiquitin E3 ligase(s) that is absent from dopaminergic neurons. Such candidate(s) redundant E3-ligase would be expected to fulfill several criteria: (1) bind similar E2 Ubiquitin conjugating enzymes; (2) interact with the same cellular substrates; (3) facilitate the formation of aggresome/lewy bodies with similar properties of those induced by Parkin; (4) be expressed in the nervous system but presumably absent (or largely absent) from dopaminergic neurons.

In this thesis I have demonstrated that the Human Homolog of Drosophila Ariadne-1 (HHARI) is a candidate for such a redundant E3 ligase. In addition I have shown that even though HHARI induces the formation of LB like aggresomes in cell culture with properties similar to those produced by Parkin, these aggresomes differ in their detergent solubility properties.

Using mouse C2C12 primary skeletal muscle cells with altered expressions of Ariadne-1 or Parkin, I determined if HHARI and Parkin may serve redundant protective roles. Using cell viability assays I have shown that HHARI does not confer protection to cells treated with toxic insults like those implicated in PD. On the contrary, using RNA silencing, I have shown that reduced Ariadne-1 expression appears to confer some benefit.

Finally, based on phenotypes reported for Ariadne-1-/- escaper and Parkin-/- flies as well as our protein interaction data, I investigated the roles of Parkin and HHARI during myogenesis. Using engineered C2C12 cells I have shown that Ariadne-1 levels are tightly regulated in proliferating and differentiating C2C 12 cells and that increased cellular abundance of Ariadne-1 affects muscle terminal differentiation downstream of myogenin, strongly highlighting the importance of Ariadne-1 and perhaps the Ubiquitin Proteasome Pathway in myogenesis.

Indexing (details)


Subject
Neurology;
Cellular biology
Classification
0317: Neurology
0379: Cellular biology
Identifier / keyword
Biological sciences; Apoptosis; Ariadne-1; Muscle; Parkin; Parkinson's disease; Ubiquitin
Title
The ubiquitin E3 ligase Human Homolog of Drosophila Ariadne-1 (HHARI) is a structural and functional homolog of Parkin and is required for myogenesis
Author
Parelkar, Sangram S.
Number of pages
153
Publication year
2008
Degree date
2008
School code
0118
Source
DAI-B 69/07, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549663843
Advisor
Schwartz, Lawrence M.
Committee member
Hebert, Daniel N.; Langford, George M.; Osborne, Barbara A.
University/institution
University of Massachusetts Amherst
Department
Molecular & Cellular Biology
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3315506
ProQuest document ID
304566333
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304566333
Access the complete full text

You can get the full text of this document if it is part of your institution's ProQuest subscription.

Try one of the following:

  • Connect to ProQuest through your library network and search for the document from there.
  • Request the document from your library.
  • Go to the ProQuest login page and enter a ProQuest or My Research username / password.