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SYNAPTIC DEFECTS IN SPINAL MUSCULAR ATROPHY
by
Kar Yun Karen Ling
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
December 2011
Copyright 2011 Kar Yun Karen Ling
Object Description
| Title | Synaptic defects in spinal muscular atrophy |
| Author | Ling, Kar Yun Karen |
| Author email | karling@usc.edu;kkyling@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2011-09-22 |
| Date submitted | 2011-10-27 |
| Date approved | 2011-10-27 |
| Restricted until | 2012-10-27 |
| Date published | 2012-10-27 |
| Advisor (committee chair) | Ko, Chien-Ping |
| Advisor (committee member) |
Baudry, Michel Butler, Samantha J. Reddy, Sita |
| Abstract | Spinal Muscular Atrophy (SMA), an autosomal recessive neurodegenerative disease, is a leading genetic cause of infant mortality. The major clinical symptoms are muscle weakness and paralysis. Prevailing thinking is that muscle weakness is caused by muscle denervation subsequent to motoneuron degeneration. However, the exact cellular events leading to the motor impairment are not fully understood. In this study, we used a mouse model for SMA to examine the synaptic components in the central and peripheral nervous system that are important for motor functions. We uncovered a selective vulnerability of neuromuscular junctions (NMJs) to denervation in SMA mice. The selectiveness to denervation is not attributed to muscle fiber types, muscle locations or spinal segments in which motoneurons reside. In addition to NMJ denervation, a significant loss of proprioceptive inputs on spinal motoneurons of SMA mice may contribute to muscle weakness in the hindlimb muscles that were denervated throughout the disease progression. These studies suggested that synapse loss occur extensively in both the peripheral and central nervous system, which may contribute to the muscle weakness in SMA mouse model. Besides defects in synapse connectivity, compromised synapse maturity was also revealed in this SMA mouse model. Using isolated muscle culture, we identified a muscle-intrinsic defect that could contribute to synapse immaturity. Our studies suggested that SMA is a disease involving synapses in central and peripheral nervous systems, both neuronal and non-neuronal targets. Our studies provide insights on designing therapeutics on multiple targets in SMA. |
| Keyword | spinal muscular atrophy; SMA; neurodegenerative disease; neuromuscular junction; neuromuscular disease; synapse; motoneuron |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Ling, Kar Yun Karen |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@lib.usc.edu |
| Archival file | uscthesesreloadpub_Volume71/etd-LingKarYun-367.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | SYNAPTIC DEFECTS IN SPINAL MUSCULAR ATROPHY by Kar Yun Karen Ling A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) December 2011 Copyright 2011 Kar Yun Karen Ling |
