Ubiquitin proteasome pathway, autophagy and a novel therapeutic approach to prevent neurodegeneration linked to inflammation in ALS
Item
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Title
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Ubiquitin proteasome pathway, autophagy and a novel therapeutic approach to prevent neurodegeneration linked to inflammation in ALS
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Identifier
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d_2009_2013:0c6490d6c366:10931
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identifier
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11170
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Creator
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Myeku, Natura,
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Contributor
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Maria E. Figueiredo-Pereira
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Date
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2011
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Language
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English
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Publisher
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City University of New York.
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Subject
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Molecular biology | Cellular biology | Neurosciences | Autophagy | cAMP/PKA | Neurodegeneration | Neuroinflammation | Spinal Cord | Ubiquitin Proteasome Pathway
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Abstract
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Neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases as well as amyotrophic lateral sclerosis (ALS), are a heterogeneous group of clinical disorders characterized by the selective loss of neurons in specific regions of the CNS. Despite their variability they have similar features including the accumulation of proteins that develop into inclusion bodies. Ubiquitinated proteins are major components of these inclusions suggesting that impaired proteasome activity and/or dysfunction of the ubiquitination pathway may be main players in this process. Emerging data reveal that autophagosomes are also components of inclusion bodies, implicating autophagy in neurodegenerative disorders as well.;The research described in this thesis led to two discoveries: 1) The UPP, not autophagy, is the main pathway implicated in the degradation of soluble ubiquitinated proteins. Furthermore, proteasome impairment, and not autophagy dysfunction, causes the intracellular accumulation/aggregation of ubiquitinated proteins..;We demonstrate that proteasome impairment leads to accumulation of ubiquitinated proteins. Most importantly, inhibition of autophagy failed to cause ubiquitin protein accumulation. We also established that the soluble p62/sqstm1, a polyubiquitin shuttling factor, is associated with the proteasomes and not with autophagosomes. It is thought that p62/sqstm1 delivers polyubiquitinated proteins to proteasomes and/or autophagosomes for degradation. From a therapeutic point of view our data support the notion that pharmacological means to sustain or enhance proteasome activity and p62/sqstm1 levels could be an efficacious strategy to remove ubiquitinated proteins and prevent or delay the onset of neurodegeneration associated with protein aggregation.;2) The activity of the proteasome and the levels of p62/sqstm1 are significantly enhanced by dibutyryl-cAMP in spinal cord cultures..;We demonstrate that db-cAMP enhances the activity of the proteasome and p62/sqstm1 levels. Furthermore, pre-treatment of the neuronal cultures with db-cAMP mitigate cell toxicity induced by prostaglandin J2 (PGJ2). PGJ2 is an inflammatory mediator found to be elevated in post mortem slices of spinal cord motor neurons in ALS patients. Our data support the notion that enhancing of proteasome activity by the cAMP/PKA pathway provides an effective neuroprotective strategy against ALS and other neurodegenerative diseases associated with proteinaceous aggregates and signs of neuroinflammation.;In conclusion, our data support that impaired proteasome activity occupies the center stage in the development of neurodegenerative diseases. Enhancing proteasome activity can have therapeutic implications in drug development aiming at prevention and treatment of neurodegenerative disorders.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
