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Pregnancy Associated Plasma Protein-aa Is a Novel Regulator of Neuron Survival.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Pregnancy Associated Plasma Protein-aa Is a Novel Regulator of Neuron Survival./
作者:	Alassaf, Mroj.
面頁冊數:	1 online resource (147 pages)
附註:	Source: Dissertations Abstracts International, Volume: 82-07, Section: B.
Contained By:	Dissertations Abstracts International82-07B.
標題:	Neurosciences. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28264401click for full text (PQDT)
ISBN:	9798557060219

Pregnancy Associated Plasma Protein-aa Is a Novel Regulator of Neuron Survival.
Alassaf, Mroj.

Pregnancy Associated Plasma Protein-aa Is a Novel Regulator of Neuron Survival. - 1 online resource (147 pages)

Source: Dissertations Abstracts International, Volume: 82-07, Section: B.

Thesis (Ph.D.)--The University of Wisconsin - Madison, 2021.

Includes bibliographical references

Neuron loss compromises the function of the nervous system and is a hallmark of neurodegenerative disorders. Mitochondria are critically important for cell survival. Despite the diverse etiologies of neurodegenerative disorders, a common underlying feature is mitochondrial dysfunction. Therefore, identification of inherent molecular and genetic mechanisms that regulate mitochondrial function may provide promising therapeutic targets. Through characterization of a zebrafish mutant, we have identified a novel regulator of mitochondrial function and neuron survival: Pregnancy Associated Plasma Protein-aa (Pappaa). pappaa encodes a secreted metalloprotease that stimulates the local availability of insulin-like growth factor 1 (IGF1) by cleaving IGF binding proteins, thereby freeing IGF1 to bind to its receptor. Although IGF1 has been extensively studied within the context of cell survival, little is known about how IGF1 is regulated to promote cell survival, and whether it impacts essential organelle function. My dissertation aims to answer these questions. In chapter 2, we demonstrate that loss of Pappaa causes mitochondrial dysfunction in zebrafish lateral line hair cells. We show that pappaa mutant hair cells have a buildup of mitochondrial calcium and exhibit altered activity. pappaa mutant hair cells also show elevated levels of mitochondrial ROS, suggesting that Pappaa acts to attenuate mitochondria-generated ROS. Furthermore, we show that pappaa mutant hair cells are more vulnerable to pharmacological stimulation of mitochondrial ROS production, supporting the idea that pappaa mutant hair cells are predisposed to ROS-induced death. Exposure to an IGFBP inhibitor improved hair cell survival in pappaa mutants following pharmacological induction of ROS; and conversely, attenuation of IGF1 signaling in wild type larvae reduced hair cell survival. Taken together, our results suggest that Pappaa promotes hair cell survival by regulating mitochondrial function through the IGF1 signaling pathway. In chapter 3, we provide evidence supporting a model by which Pappaa regulates mitochondrial calcium load, and thereby mitochondrial function, by regulating the endoplasmic reticulum (ER)-mitochondria axis. pappaa mutant hair cells showed excessive and abnormally close ER-mitochondria contacts, suggesting enhanced ER-mitochondria calcium transfer. In support of this, pappaa mutant hair cells showed increased vulnerability to pharmacological induction of ER-mediated calcium release. Furthermore, we show that processes downstream of the ER-mitochondria axis are disrupted by Pappaa loss of function. pappaa mutant hair cells show mitochondrial fragmentation and reduced autophagic flux. The ER-mitochondria connection can be altered by ER stress. We show that pappaa mutant hair cells have an active unfolded protein response indicating ER stress. In chapter 4, we reveal that Pappaa is required for motor neuron survival. Pappaa-deficient motor neurons die prematurely. Gene expression analysis revealed upregulation of antioxidants indicating oxidative stress. Treatment with an IGFBP inhibitor rescues motor neuron degeneration in pappaa mutant larvae, suggesting that Pappaa regulates motor neuron survival by stimulating the IGF1 signaling pathway. Overall, work presented in this dissertation uncovers a novel role for Pappaa in promoting neuron survival by regulating the ER-mitochondria connection, mitochondrial function, and oxidative stress.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798557060219Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

ER stressIndex Terms--Genre/Form:

542853
Electronic books.

Pregnancy Associated Plasma Protein-aa Is a Novel Regulator of Neuron Survival.
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