The Role of AlphaB-crystallin During Peripheral Nerve Regeneration
Abstract
This dissertation characterizes the role of a small heat shock protein called alphaB-crystallin (αBC) in peripheral nerve regeneration. Peripheral nerve injuries are fairly common and often result in patient disability due to the partial and incomplete regeneration of nerves. The expression of αBC in the peripheral nervous system (PNS) has been known, but its role has not been determined. Because many protective and beneficial functions of the heat shock protein has been reported in a variety of cells and models, I explored whether αBC also has a beneficial role in the PNS particularly after sustaining an injury. Using 129S6 wild-type (WT) and αBC null (αBC-/-) mice, I discovered that αBC positively influenced PNS regeneration. Following sciatic nerve crush, I found that αBC-/- mice had decreased functional recovery, slower motor nerve conduction velocities, and thinner myelin sheaths 28 days post-injury. I additionally observed higher numbers of macrophages (mΦ) in the distal sciatic nerves of αBC-/- mice during the late time points post-injury that may explain the heightened sensitivity towards mechanical and thermal stimulation observed in these animals. I further elucidated that the injury deficits observed in the αBC-/- mice were due to aberrant neuregulin-1/ErbB2 and pAkt signaling. Cumulatively, these findings indicate that αBC positively modulates peripheral nerve regeneration by promoting remyelination and mediating clearance of macrophages in the distal nerve. Lastly, because of reduced expression of αBC with increasing age, I investigated whether αBC plays a role in deficits associated with the aging PNS. I found that αBC-/- mice displayed thinner myelin sheaths before and after injury at different ages. Moreover, 12-month-old αBC-/- mice displayed higher numbers of macrophages before and after injury and, lower numbers of squalene monooxygenase (SQLE), an important enzyme in cholesterol synthesis. These findings are consistent with previous reports that revealed in the aging PNS there is upregulation of genes associated with inflammation and downregulation of genes associated with lipid metabolism. Further exploration is needed to identify the mechanisms involved. Collectively, the work presented in this dissertation provides novel evidence of the significant roles of αBC following peripheral nerve injury.
Description
Keywords
Neuroscience
Citation
Lim, E. (2016). The Role of AlphaB-crystallin During Peripheral Nerve Regeneration (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28318