Molecular characterization of mutations in the small heat shock proteins associated with inherited peripheral neuropathies
5 December 2016
UAntwerp, Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken
4:15 PM - 6:15 PM
PhD defence Thomas Geuens - Department of Biomedical Sciences
The inherited peripheral neuropathies (IPN) consist of a large and heterogeneous group of disorders typically affecting the peripheral nervous system (PNS). The IPN are characterized by a length-dependent and progressive degeneration of motor and or sensory nerves. Among the IPN, Charcot-Marie-Tooth’s disease (CMT) is the most common subgroup with an estimated prevalence of 1 in 2500 individuals. While both the motor and sensory nerves are affected in CMT neuropathies, the motor neurons are predominantly affected in distal hereditary motor neuropathies (dHMN).
In both diseases the neurodegeneration causes distal muscle weakness and atrophy in the feet and legs, and may extend to the hands and arms. Currently, more than 1500 different mutations in more than 80 disease-causing genes have been identified for IPN. Among these are genes coding for small heat shock proteins (HSPB1 and HSPB8), in which mutations have been found to cause axonal variants of CMT and/or dHMN. Both proteins are important molecular chaperones that protect aggregated and misfolded proteins from degradation. Depending on where the mutation is located it can lead to CMT and/or dHMN. To further understand this discrepancy I focused in the first part of my thesis on a specific C-terminal HSPB1 mutation that causes a severe type of dHMN. I identified that the wild type HSPB1 protein is able to bind to the poly(C)binding protein 1 (PCBP1), which is an RNA binding protein, and that mutant HSPB1 forms an increased interaction. This negatively affects the translational repressive activity of PCBP1 consequently leading to an altered expression profile of genes known to be associated with IPN.
In a second part of my thesis I studied the role of HSPB1 and HSPB8 in the formation of stress granules, a biological process that occurs upon cellular stress, which protects mRNAs from degradation. This study reports that HSPB1, but not HSPB8, is present in stress granules. Interestingly, HSPB1 seems not to be crucial for the formation of stress granules and mutant HSPB1 proteins are not present in stress granules under basal conditions but get recruited to them upon heat shock without any alteration in its formation.
In the last part of the thesis I contributed to the largest epidemiologic and phenotypic study of dHMN performed so far. Functional studies performed on 5 novel HSPB1 and 3 novel HSPB8 mutations further demonstrate the pleotropic character of these small heat shock proteins.