Inactivation of Magel2 in a mouse model of Prader-Willi Syndrome alters autophagy in the hypothalamus and impairs muscle function

  • Author / Creator
    Kamaludin, Ain A
  • Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder causing severe neonatal hypotonia that persists until adulthood, reduced muscle mass, and hyperphagia leading to childhood-onset obesity. PWS is caused by inactivation of several genes located on chromosome 15q11-q13, including MAGEL2. MAGEL2 promotes endosomal protein trafficking through its interaction with TRIM27, an E3 RING ubiquitin ligase, and may also be important for delivering targeted proteins to lysosome to be degraded by a process known as autophagy. Mouse Magel2 is predominantly expressed in the central nervous system, with higher expression in the hypothalamus, a key region in the brain that is responsible in regulating appetite and energy homeostasis. Loss of Magel2 in mouse causes increased adiposity and reduced muscle mass, recapitulating abnormal phenotypes seen in people with PWS. Therefore, I hypothesize that MAGEL2 plays a significant role in protein degradation by autophagy as well as regulation of body weight and muscle function. I determined that autophagy is dysregulated in specific hypothalamic neurons of Magel2-null mice. This was measured as a decrease in expression of p62, a protein that links targeted proteins for lysosomal degradation, and expression of ubiquitinated proteins in the neurons of mice lacking Magel2. Furthermore, Magel2-null mice have reduced muscle mass accompanied by changes in the muscle fiber size distribution, where a shift towards smaller fiber size was seen in gastrocnemius but a shift towards bigger fiber size was seen in soleus. No significant morphological changes were observed in Magel2-null muscles despite reduced muscle mass and changes in fiber size distribution. Loss of Magel2 in muscle results in increased protein degradation associated with both an upregulation of MuRF1, a gene that regulates degradation of myofibrillar proteins, and increased p62 aggregates. Taken together, Magel2 is required to maintain normal autophagic rate in hypothalamic neurons and plays important roles in regulating muscle structure and function. Better understanding of the cellular function of MAGEL2 in neuronal and muscle cells, and its connection with autophagy can be used to develop therapeutic treatments targeting neuronal autophagy, as well as muscle function and structure in children with PWS who lack MAGEL2 expression.

  • Subjects / Keywords
  • Graduation date
    Fall 2016
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.