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Autophagy and stress granules: The m...

Trengrove, Chelsea Brais.

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Autophagy and stress granules: The merging of two pathways in Parkinson's disease.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Autophagy and stress granules: The merging of two pathways in Parkinson's disease./
作者:	Trengrove, Chelsea Brais.
面頁冊數:	128 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-07(E), Section: B.
Contained By:	Dissertation Abstracts International77-07B(E).
標題:	Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10016944
ISBN:	9781339499031

Autophagy and stress granules: The merging of two pathways in Parkinson's disease.
Trengrove, Chelsea Brais.

Autophagy and stress granules: The merging of two pathways in Parkinson's disease. - 128 p.

Source: Dissertation Abstracts International, Volume: 77-07(E), Section: B.

Thesis (Ph.D.)--Boston University, 2016.

Autophagy is compromised in Parkinson's disease (PD) with a number of PD-associated genetic mutations leading to its dysregulation. Leucine-rich repeat kinase (LRRK2) mutations, causative of PD, aberrantly enhance autophagy. Our lab elucidated a LRRK2 gene regulatory network identifying transcripts showing coordinated expression level changes associated with PD. Histone deacetylase 6 (HDAC6) was found to be an important interactor with LRRK2, regulating many of the same transcripts. The majority of these transcripts associate with autophagy and the lysosomal complex. I hypothesized that LRRK2 interacts with HDAC6 to regulate autophagy. Silencing of HDAC6 in SH-SY5Y normalized the autophagosomal size altered by expression of PD-linked LRRK2 mutants. This work identified a key role for HDAC6 in mediating the autophagic dysfunction induced by the mutant LRRK2. In addition to autophagy, stress granule (SG) formation has emerged as a compelling mechanism in the pathogenesis of PD. RNA-binding proteins (RBPs), such as T-cell intracellular antigen-1 (TIA-1), are major component of SGs. I observed TIA-1 translocating from the nucleus to the cytoplasm in PD cortex without forming SGs. Hu antigen D (HuD) also showed changes, with the RBP more present in the cytoplasm than the nucleus in PD with no SGs observed. These preliminary studies lead to the hypothesis that low levels of SGs result from an inhibition by alpha-synuclein (syn), or hyperactive autophagy. For that purpose, brain tissues from a mouse model of PD (A53T-syn transgenic mouse) were examined by immunohistochemistry. There was no difference in TIA-1 expression in control and A53T-syn expressing mouse brains, or SG formation in primary neurons after treatment with recombinant A53T fibrils. To determine whether the lack of SGs in PD brain was due to activation of autophagy, BE-M17 cells were treated with rapamycin, an autophagy activator, which decreased SGs by 50%. Overexpression of TIA-1 in BE-M17 cells under arsenite treatment also increased autophagosomal size by 50%, indicating co-regulation of SGs and autophagy. My work indicates that the pathophysiology of PD is associated with a loss of SGs due to elevated activity of autophagy, presumably due to PD-linked LRRK2 mutations. This co-regulatory network may be a potential therapeutic target of PD.

ISBN: 9781339499031Subjects--Topical Terms:

634543
Pharmacology.

Autophagy and stress granules: The merging of two pathways in Parkinson's disease.
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