Doctoral Dissertation Proposal Presentation in Biological Sciences: Ibtissem Derouiche 5/24

The Kennedy College of Sciences Department of Biological Sciences invites you to attend a doctoral dissertation proposal defense by Ibtissem Derouiche on “How does Neurofilament Phosphorylation Regulate Axonal Outgrowth in Stabilization?” 

Candidate Name: Ibtissem DerouicheD
Degree: Doctoral Dissertation Proposal Defense
Defense Date: Friday, May 24, 2024
Time:  11 a.m.
Location: Ball Hall 302 

Committee Members:

Brief Abstract:

Neurological disorders result in 9.4 million deaths worldwide. Neurofilaments (NFs) are tissue-specific intermediate filaments that maintain neuronal structural stability. Mammalian NFs are composed of Heavy (NF-H), Medium (NF-M), and Light (NF-L) subunits, named according to their molecular mass, along with α-internexin or peripherin (in central or peripheral nervous systems, respectively) NF subunits assemble linearly, with C-terminal regions extending from the filament “backbone.” Phosphorylation of C-terminal “side arms” of NF-H promotes NF-NF interactions, providing stability to axons. Alterations in these interactions promote neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Charco-Marie-Tooth disease, and Giant Axonal Neuropathy. Transport of NFs from the cell body into the axon and NF-NF interactions are dependent upon regulation of multiple kinases. The complete sequence of phosphorylation events does not occur until NFs have entered the axon. Notably, prior to phosphorylation, NFs are proteolyzed by calpain raising the question: How are NFs protected from proteolysis within perikarya and during axonal transport?

Sidearm phosphorylation fosters lateral extension away from the NF backbone.  By contrast, sidearm conformation prior to phosphorylation remains unresolved. Scrutiny of the NF-H side-arm sequence revealed 4 proline-proline (PP) motifs; these motifs allow tremendous rotation of their peptide chains from from a closed, folded-back hairpin (cis) to a fully extended, linear confirmation (trans). Notably, one PP motif is located within each of the consensus sequences for the NF kinases.  

We hypothesize that phosphorylation-induced alterations in the configuration of these PP motifs are critical for NF transport, NF-NF interaction and susceptibility of NFs to proteolysis.    We will test this hypothesis by expression and interaction of targeted mutations of NF-H.

All interested students and faculty members are invited to attend.