Research team
Molecular biological research of HSPB8 mutations in relation to hereditary neuron disorders.
Abstract
The distal hereditary motor neuropathies (HMN) are a heterogeneous group of disorders characterized by the selective degeneration of motor neurons of the peripheral nervous system. Two disease causing genes, HSPB8 and HSPB1, were identified in our group for distal HMN type II. These genes belong to the super family of the small heat shock proteins (sHSPs). In this project we try to find an answer to the question why mutations in HSPB8 selectively affect peripheral motor neurons. Through in vitro cellular studies we investigate the functional consequences of mutations in HSPB8. Furthermore we will generate a knock-in mouse model to analyse the pathomechanism directly.Researcher(s)
- Promoter: Timmerman Vincent
- Co-promoter: Irobi Joy
- Fellow: Holmgren Anne
Research team(s)
Funding
- IWT
Project type(s)
- Research Project
Molecular biology research of HSPB8 mutations associated with hereditary motor neuropathy.
Abstract
Our main research question is why do mutations in HSPB8 predominantly affect the the peripheral neurons while the other cell types which express equally the mutant HSPB8 are spared. Small HSPs can protect the cell from stress situations by: (1) binding to unfolded proteins, (2) regulating apoptosis and (3) stabilizing the cytoskeletal network. The effects of mutation on the function and interaction properties of HSPB8 are not completely understood. Mutation in sHSPs could disrupt the interaction pathways via the formation of protein accumulation (aggregates). The biological relevance of mutant HSPB8 protein aggregation in vivo (spinal cord) still needs to be confirmed. It is plausible that mutant protein aggregation could induce changes in the neurofilament network and disturb axonal transport. The axonal transport in the peripheral neurons is essential for the retrograde and anterograde transport of proteins, cargos and vesicles along the microtubules. Spinal motor neuron consists of the longest axons which innervate the most distal muscles; it is possible that changes in the axonal cargo transport could contribute to the development of peripheral neuropathy. Despite the fact that studies of biological processes in cell culture will yield useful information, generation of animal models are essential towards understanding the pathological mechanism, and the possibility to study the effects of potential drug therapy. Of note is that an animal model, for example a mouse model, will enable us to study the two most important cell types involved in peripheral neuropathy, the neurons and Schwann cells.Researcher(s)
- Promoter: Irobi Joy
Research team(s)
Funding
- FWO
Project type(s)
- Research Project
Molecular genetics and functional study of HSPB8 mutations associated with hereditary motor neuropathy.
Abstract
In this proposal, I intend to obtain better insights into the precise mechanisms underlying mutant HSPB8 protein resulting in specific neuronal degeneration. Our hypothesis is that distal HMN might be as a result of cell death of peripheral neurons due to aggregation and abnormal interaction of mutant HSPB8 protein. Mutant protein could interfere with the cytoskeleton network and axonal transport pathways, and this could ultimately lead to perikaryal atrophy and axonal loss. Another mechanism might be the impairment of energy production along this specialized axon which might alter axoplasmic transport activities or led to synaptic dysfunction.Researcher(s)
- Promoter: Timmerman Vincent
- Fellow: Irobi Joy
Research team(s)
Funding
- FWO
Project type(s)
- Research Project
Molecular biological research of HSPB8 mutations in relation to hereditary neuron disorders.
Abstract
The distal hereditary motor neuropathies (HMN) are a heterogeneous group of disorders characterized by the selective degeneration of motor neurons of the peripheral nervous system. Two disease causing genes, HSPB8 and HSPB1, were identified in our group for distal HMN type II. These genes belong to the super family of the small heat shock proteins (sHSPs). In this project we try to find an answer to the question why mutations in HSPB8 selectively affect peripheral motor neurons. Through in vitro cellular studies we investigate the functional consequences of mutations in HSPB8. Furthermore we will generate a knock-in mouse model to analyse the pathomechanism directly.Researcher(s)
- Promoter: Timmerman Vincent
- Co-promoter: Irobi Joy
- Fellow: Holmgren Anne
Research team(s)
Funding
- IWT
Project type(s)
- Research Project
Molecular genetics and biology of mutations in small heat shock proteins HSP22 and HSP27 in relation to motor neuropathies.
Abstract
Distal hereditary motor neuropathies (distal HMN) are genetically and clinically heterogeneous diseases of the peripheral nervous system (PNS). We recently found pathogenic mutations in two small heat shock proteins HSP22 and HSP27 as a cause for distal HMN. This projects aims: 1. Genotype-phenotype correlations in distal HMN and other inherited diseases of the PNS, 2. Association studies of HSP22 and HSP27 as risk or protective factors for amyotrophic lateral sclerosis (ALS), 3. Functional analysis of HSP22 and HSP27 mutations, 4. Construction of transgenic mice overexpressing specific HSP22 and HSP27 mutations.Researcher(s)
- Promoter: Irobi Joy
Research team(s)
Funding
- BOF
Project website
Project type(s)
- Research Project
Identification of the gene for distal hereditary motor neuropathy type II.
Abstract
Distal hereditary motor neuropathies (distal HMN, MIM#158590) are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles[1]. We recently ascertained a large Czech family with 34 affected individuals with a phenotype strikingly similar to the previously reported Belgian distal HMN II family[2]. In both families we performed a haplotype analysis and identified several recombinants reducing the locus from 5 Mb[2] to 1.7 Mb. From this refined region we excluded several genes [3;4], and recently, identified two missense mutations (K141N and K141E) occurring in the same codon, within the ¿-crystallin domain of the small heat shock protein 22 (HSP22) gene. A c.423G>C (K141N) mutation was identified in Belgian CMT-M and Czech CMT-196 pedigrees while the second mutation, c.421A>G (K141E) was found in Bulgarian AJ-12 and English CMT-355 families. Both HSP22 mutations were absent in 400 Caucasian control chromosomes. Since the Belgian/Czech and Bulgarian/English shared respectively the K141N and K141E mutations, we performed haplotype analysis, and the results suggest that all families are genetically not closely related[5]. Both mutations target the same amino acid critical for the structural and functional integrity of the sHSP ¿A-crystallin[6]. This positively charged residue, when mutated in other sHSP gene members, results in various human disorders[7],[8]. Co-immunoprecipitation showed an increased binding of both HSP22 mutants to the interacting partner HSP27. Expression of mutant HSP22 in cultured cells promoted formation of intracellular aggregates. Our findings provide further evidence that mutations in heat shock proteins play an important role in neurodegenerative disorders.Researcher(s)
- Promoter: Irobi Joy
Research team(s)
Funding
- BOF
Project type(s)
- Research Project
Molecular biology of small heat shock protein HSP22 en HSP27 mutations in relation to distal hereditary motor neuropathies.
Molecular genetic and functional analysis of heat shock protein 22 (HSP22) mutations associated with distal hereditary motor neuropathy.
Abstract
Researcher(s)
- Promoter: Timmerman Vincent
- Fellow: Irobi Joy
Research team(s)
Funding
- BOF
- FWO
Project type(s)
- Research Project
VIB-Molecular biological aspects of neurogenic muscular atrophy.
Abstract
Researcher(s)
- Promoter: Timmerman Vincent
- Co-promoter: Irobi Joy
Research team(s)
Funding
- PRIVE - non profit
Project type(s)
- Research Project