The molecular composition and localization of Dystrophin-Associated Protein Complexes and ε-sarcoglycan in mammalian brain.

Nathalie Parolaro

Research output: ThesisDoctoral Thesis

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Abstract

Duchenne muscular dystrophies (DMD) arise from mutations in the DMD
gene. In the brain, the DMD gene product, dystrophin, localizes at the post-synaptic density (PSD) of inhibitory GABAergic neurons (Brunig et al, 2002). PSDs are specialised cytoskeletal structures that underlie and are attached to the post-synaptic membrane. In PSDs of the brain, dystrophin is part of a multi-protein complex, namely the dystrophin-associated protein complex (DPC) found exclusively at GABAergic synapses. Recent studies have identified a novel alternatively spliced dystrophin product in the brain, referred to as delta dystrophin, whose molecular associations and functions are unknown. In this thesis I have investigated whether delta dystrophin may form novel DPC complexes at GABAergic synapses of the brain. Results suggest that in the brain,
delta dystrophins exhibit different regional and subcellular distributions when compared to classical dystrophins and do not co-localise with any of the PSD markers or DPC components tested. Rather, delta dystrophins fully co-localise with b3-tubulin, a component of the microtubule (MT) cytoskeleton. These studies suggest, that unlike classical dystrophin, delta dystrophin is likely to form novel delta DPC complexes outside rather than within the GABAergic synapse, and therefore may have a different molecular composition and function compared to classical dystrophin-containing DPC complexes. Therefore, delta dystrophin co-localisation with the MT network may provide a potential novel route by which cognitive pathology in DMD patients may be initiated.
e-sarcoglycan, is a well-established DPC component in smooth muscle. However, the present studies suggest that it may not be a component of classical and delta dystrophin-containing DPC complexes at GABAergic synapses and microtubule structures, respectively. Its membrane localization suggests e-sarcoglycan is likely to be part of novel, yet unidentified complexes in the brain. However, attempts to raise high affinity antisera that could be used to purify and characterize e-sarcoglycan complexes were unsuccessful.
Original languageEnglish
QualificationPh.D.
Awarding Institution
  • Royal Holloway, University of London
Supervisors/Advisors
  • Beesley, Philip, Supervisor
  • Alifragis, Pavlos, Advisor
Thesis sponsors
Award date1 Jan 2013
Publication statusUnpublished - 2012

Keywords

  • Nathalie Parolaro
  • Dystrophin-Associated Protein Complex
  • epsilon sarcoglycan
  • Royal Holloway University of London

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