Autophagy in inherited peripheral neuropathies: Focus on the small heat shock protein HSPB1
29 March 2018
Promotiezaal (UAntwerp, Campus Drie Eiken, Building Q) - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken
4:00 PM - 6:00 PM
PhD defence Mansour Haidar - Department of biomedical sciences
Inherited peripheral neuropathies (IPNs) are genetically heterogeneous disorders with over 1500 mutations in more than 80 affected genes discovered so far. IPNs are characterized by length-dependent degeneration affecting the motor and/or sensory nerves and leading to a varied range of severity, from mild motor or sensory impairment to self-mutilation and wheelchair dependency. Given the increasing heterogeneity among IPN-associated genes, recent functional research studying the pathogenic mechanisms of IPNs has focused on identifying common pathomechanisms underlying the IPN pathology. In the last few years several studies have shown a correlation of IPN-associated genes with autophagy, a cellular homeostatic process required for the removal of cell aggregates, long-lived proteins and dead organelles. Among the genes associated with IPNs are those coding for the small heat shock protein HSPB1, in which mutations can lead to the axonal form of Charcot-Marie-Tooth neuropathy (CMT2) and distal hereditary motor neuropathy (dHMN). Several studies have shown that HSPB1 and other members of the small heat shock protein family are capable of modulating several important cellular functions which might explain the pathogenic effects of their mutations in the context of IPNs.
In the first part of this thesis I will discuss the study we performed to monitor the effects of HSPB1 mutations on autophagy. We show that mutations in HSPB1 lead to decreased levels of autophagy. We also see that knocking-out HSPB1 also impairs the autophagy process, indicating that it is an essential player in the autophagy pathway.
In the second part of the thesis I describe the interactomics study we performed to have an in-depth view of the interactors of wild type and mutant HSPB1 in the context of autophagy. Through an extensive proteomic analysis we identified interactors associated with the autophagy process. Then after further validation, we reveal the autophagy receptor P62/SQSTM1 as an interactor of HSPB1. We show that the interaction of mutant HSPB1 with P62 affects its autophagy function, leading to a decreased capacity to form P62 bodies, and impairment of phagophore formation.
This work provides an insight into the role of HSPB1 as a regulator of autophagy through interaction with P62 and presents the impairment of autophagy as one of the pathomechanisms by which mutations in HSPB1 lead to peripheral neuropathy.