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Identification of Potential HTT-Rab Axonal Transport Complexes
Başlık:
Identification of Potential HTT-Rab Axonal Transport Complexes
Yazar:
White, Joseph Allen, II, author. (orcid)0000-0003-4914-9140
ISBN:
9780438050174
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (189 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Shermali Gunawardena Committee members: Paul Cullen; Kathryn Medler; Matthew Xu-Friedman.
Özet:
Huntington's disease (HD) is a deadly neurodegenerative disorder that is caused by an expansion of the poly-glutamine tract in the huntingtin (HTT) gene. Evidence has shown that HTT can function in the axonal transport pathway, but the exact role of HTT during axonal transport is unclear. We found that HTT differentially regulates the axonal transport of a subset of Rab-containing vesicles within axons (Chapter 2). Reduction of endogenous Drosophila HTT perturbed the bi-directional motility of Rab3, Rab4, and Rab19, disrupted the retrograde motility of Rab7, and, stimulated the anterograde motility of Rab2 within axons. Dual-color imaging revealed that HTT co-migrates with these Rabs within axons in vivo. Further analysis revealed that Rab4 and HTT co-migrate with synaptic vesicle proteins synaptobrevin and synaptotagmin suggesting that HTT-Rab4 is likely on synaptic vesicles (Chapter 3). Rab4 immunoprecipitated with HTT and the kinesin-1 motor subunit KIF5C indicating that the HTT-Rab4 complex associates with motors. We also identified that HTT-interacting proteins and Rab-interacting proteins are involved in the axonal movement of the HTT-Rab4 complex. We propose that the soluble HTT-interacting protein, HIP14, aids in the membrane localization of HTT. HIP1, a membrane bound HTT-interacting protein, is likely present with the HTT-Rab4 moving complex and the Rab-interacting protein Rip11 is also found with Rab4 and HTT. Intriguingly, a moving HTT-Rab4 complex also exists in mammalian neurons and is disrupted in neurons derived from HD patient iPSCs. Taken together, our results identify a moving HTT-Rab4-motor complex during axonal transport which is disrupted by the expansion of polyQ repeats in HTT.
Notlar:
School code: 0656
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(682060.1) | 682060-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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