Browsing by Subject "Neurodegenerative Diseases"
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Item Herp Reduces ER Calcium Content by Proteasomal Degradation of SERCA(2008-08-08) Mao, Yuntao Steve; Kodadek, Thomas J.Herp, an endoplasmic reticulum (ER) stress inducible protein, reduces ER Ca2+ content in neurons and prevents their apoptosis. An understanding of the mechanism by which Herp decreases ER Ca2+ content requires studies of Herp interacting proteins, which could be SERCA and the proteasome. Herp may recruit the proteasome from the cytosol to the ER membrane, thereby facilitating the ER associated degradation (ERAD) of SERCA. The proteasome recruitment and the subsequent degradation of SERCA reduce ER lumenal Ca2+ concentration and the Ca2+ release during ER stress which counteracts the activation of apoptosis. This proposal describes how to determine the mechanism through which Herp reduces ER Ca2+ content, how to test the proteasomal degradation of SERCA, how to illustrate the proteasome recruitment to the ER membrane, and how to demonstrate the interaction between Herp and SERCA. The work will provide a new regulatory link between ER stress and Ca2+ homeostasis. In addition, studies of the proteasomal degradation of SERCA will broaden our present understanding of the regulation of SERCA. Since dysregulation of Ca2+ homeostasis has been implicated in the pathophysiology of several neurodegenerative diseases like Alzheimer's and Huntington's, research focused on Herp may lead to insights regarding therapies for those.Item An Insight into Alpha-Synulcien's Biological Function and Its Pathogenesis in Neurodegenerative Disease(2007-08-08) Gallardo, Gilbert; Sudhof, Thomas C.The discovery of two missense mutations (A53T and A30P) in alpha -synuclein that are genetically linked to Parkinson's disease, together with alpha -synuclein being the major component in Lewy bodies, has generated extensive interest in alpha -synuclein as a key component in neurodegenerative diseases. In recent years modeling this disease in transgenic mice and flies has lead to new understandings of alpha -synuclein function and pathogenesis in neurodegeneration. In the current study we analyzed transgenic mice overexpressing human alpha -synuclein and human alpha -synuclein mutations (A53T&A30P) to; First establish these transgenic mice as a model for degenerative diseases; second to identify potential contributing factors in neurodegeneration; third to decipher a potential function of alpha -synuclein. We first established that transgenic mice expressing human variants of alpha -synuclein developed an age dependant motor dysfunction with symptom logy characteristic of Parkinson's disease. Immunohistological studies revealed the presence of alpha -synuclein inclusions and a loss of motor neurons. Biochemical analysis identified a 4-5 fold increase in ubiquitin with altered expression of proteasomal subunits, characteristic of proteasomal impairment. In addition, we identified a significant increase in amyloid beta -peptides. Protein quantification of apolipoprotein E (ApoE) a protein that has been associated with the development of Alzheimer's disease, demonstrated a 5-15 fold increase in symptomatic transgenic mice. Ablation of ApoE in alpha -synuclein transgenic mice by genetic crosses revealed a delayed onset for motor dysfunction and an overall increase in survival. ApoE deficient transgenic mice displayed a decrease in ubiquitin and amyloid beta -peptides. This study illustrates ApoE, ubiquitin and Abeta - peptides contribute to the onset and progression of the neurodegeneration in transgenic alpha -synuclein mice. Genetic crosses of transgenic alpha -synuclein with a csystine string protein-alpha (CSPalpha ) knockout mouse revealed a potential function for alpha -synuclein. CSPalpha deficient mice develop an early age neurodegenerative disease that is lethal at 3-4 months. Transgenic expression of human alpha -synuclein prevented the deleterious effects of CSPalpha deficiency. Immunofluorescence studies illustrated alpha -synuclein function in a cell autonomous manner. Biochemical analysis demonstrated CSPalpha deficient mice have impaired SNARE complexes that are partially reverted by transgenic alpha -synuclein. This study illustrates a protective function of alpha -synuclein in preventing neurodegeneration.