Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults in United States. Around 5.3 million people are estimated to be living TBI-related disability in United States alone (https://www.ninds.nih.gov). TBI is often associated with accumulation of aggregated proteins and neuronal cell death, underscoring importance of degradation pathway such as autophagy. In our study, we attempted to understand the role of autophagy in TBI-related neuronal cell death. Using lateral fluid percussion injury model in rats, we found that autophagy flux was inhibited after TBI. Importantly, we discovered that treatment with 18 amino acid TAT-Beclin1 peptide increased autophagy flux and significantly reduced neuronal cell death after TBI. Further investigation revealed the role of integrated stress response (ISR) mediated by ER stress markers ATF4, CHOP and GADD34, as well as transcription factor TFEB as mediators of neuronal cell death after TBI. TAT-Beclin1 peptide induced autophagy decreased ISR in neurons and inhibited TFEB signaling, likely due to increased AKT activity. Using LFP injury model in rats as well as cortical neuron stretch injury in vitro, we also found that impaired autophagy in TBI leads to sequestration of Wnt signal mediator Dishevelled-1 (DVL-1) in autophagosomes. Sequestration of Dvl-1 likely contributes to decreased Wnt signaling, increased GSK3 activity, and phospho-Tau buildup. Furthermore, we report that TAT-Beclin1 induced autophagy prevented Dvl-1 sequestration, decreased pTau buildup and reduced neuronal cell death. Based on these findings, we postulate that autophagy flux is inhibited after TBI, and induction of autophagy by TAT-Beclin1 is beneficial in decreasing TBI-related neuronal cell death.
Subject (authority = RUETD)
Topic
Biology
Subject (authority = ETD-LCSH)
Topic
Brain--Wounds and injuries
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_8540
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (ix, 116 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Chaitali M. Saqcena
RelatedItem (type = host)
TitleInfo
Title
Graduate School - Newark Electronic Theses and Dissertations
Identifier (type = local)
rucore10002600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
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