Research Biljana Ermanoska

Abstract

Spectrins are an integral part of the submembranous cytoskeleton providing both mechanical scaffolding and organization hub for other proteins in metazoan cells. The importance of spectrins to neuronal health is demonstrated by their association with a wide range of human neurological disorders (spectrinopathies). Currently, more than forty mutations in the gene encoding non-erythroid α-spectrin (SPTAN1) are associated with developmental and epileptic encephalopathies, hereditary motor neuropathy (HMN), spastic paraplegia (HSP), and ataxia. The underlying pathomechanisms remain largely unknown. In Drosophila, the highly conserved α-spec homolog similarly plays an important role in the nervous system development, as well as in synapse formation, its function and maintenance. Interestingly, synaptic defects associated with loss of α-spec can be suppressed via neuronal mitochondria repositioning. Conversely, increased levels of α-spec rescue a range of neuronal phenotypes linked to actin-dependent mitochondrial dysfunction in an α-synuclein neurodegeneration Drosophila model. These findings suggest that modulating the levels of α-spec in neurons might have an important and understudied impact on tuning mitochondrial dynamics and preserving neuronal health. Thus, the goal of my proposal is to deepen our knowledge on how neuronal actin and spectrin cytoskeleton regulate mitochondria and assess mitochondrial dysfunction at the basis of α-spectrinopathies, using Drosophila as a model organism. My project will provide insights on whether spectrin-associated mitochondrial dysfunction is a shared or specific feature for HMN, HSP and ataxia-associated spectrin mutants. I will deploy these findings to tailor a pharmacological treatment in the α-spectrinopathy neuronal cellular models and develop a therapeutic strategy.

Researcher(s)

• Promoter: Ermanoska Biljana

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Spectrins are an integral part of the submembranous cytoskeleton providing both mechanical scaffolding and organization hub for other proteins in metazoan cells. The importance of spectrins to neuronal health is demonstrated by their association with a wide range of human neurological disorders (spectrinopathies). Currently, more than forty mutations in the gene encoding non-erythroid α-spectrin (SPTAN1) are associated with developmental and epileptic encephalopathies, hereditary motor neuropathy (HMN), spastic paraplegia (HSP), and ataxia. The underlying pathomechanisms remain largely unknown. In Drosophila, the highly conserved α-spec homolog similarly plays an important role in the nervous system development, as well as in synapse formation, its function and maintenance. Interestingly, synaptic defects associated with loss of α-spec can be suppressed via neuronal mitochondria repositioning. Conversely, increased levels of α-spec rescue a range of neuronal phenotypes linked to actin-dependent mitochondrial dysfunction in an α-synuclein neurodegeneration Drosophila model. These findings suggest that modulating the levels of α-spec in neurons might have an important and understudied impact on tuning mitochondrial dynamics and preserving neuronal health. Thus, the goal of my MSCA proposal is to deepen our knowledge on how neuronal actin and spectrin cytoskeleton regulate mitochondria and assess mitochondrial dysfunction at the basis of α-spectrinopathies, with a combined use of Drosophila as a model organism, and human iPSC-derived neurons as a platform to translate the findings to human neuronal health and disease. My project will provide insights on whether spectrin-associated mitochondrial dysfunction is a shared or specific feature for HMN, HSP and ataxia-associated spectrin mutants. I will deploy these findings to tailor a pharmacological treatment in the α-spectrinopathy neuronal cellular models and develop a therapeutic strategy

Researcher(s)

• Promoter: Baets Jonathan
• Fellow: Ermanoska Biljana

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder, affecting 1/2500 individuals worldwide. The main symptoms are progressive distal muscle weakness and wasting, sensory loss, reduced tendon reflexes, and foot and hand deformities. More than 500 mutations in over 40 genes have been implicated with this type of pathology providing more accurate CMT diagnosis. However, no effective therapies are available to treat CMT patients. Dominant intermediate CMT type C (DI-CMTC) is a recently defined CMT entity, characterized by axonal degeneration and demyelination of peripheral neurons. We were the first to describe DI-CMTC and demonstrated that it is caused by specific mutations in the gene encoding for tyrosyltRNA syntethase (YARS). This application is focused on the identification of molecular players and potential drug targets for this particular subtype of CMT. We will perform a screen for genetic modifiers of neurodegenerative phenotypes present in our recently generated Drosophila DI-CMTC model. The targeted genes will be selected based on their predicted abilities to interact with drug-like compounds. In this way, we will be able to gain original knowledge on DI-CMTC pathomechanisms and to translate it into a rational and reliable drug discovery program for this and possibly other inherited and acquired neuropathies.

Researcher(s)

• Promoter: Jordanova Albena
• Co-promoter: Timmerman Vincent
• Fellow: Ermanoska Biljana

Research team(s)

• VIB CMN - Molecular Neurogenomics

Project type(s)

• Research Project

Abstract

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder, affecting 1/2500 individuals worldwide. The main symptoms are progressive distal muscle weakness and wasting, sensory loss, reduced tendon reflexes, and foot and hand deformities. More than 500 mutations in over 40 genes have been implicated with this type of pathology providing more accurate CMT diagnosis. However, no effective therapies are available to treat CMT patients. Dominant intermediate CMT type C (DI-CMTC) is a recently defined CMT entity, characterized by axonal degeneration and demyelination of peripheral neurons. We were the first to describe DI-CMTC and demonstrated that it is caused by specific mutations in the gene encoding for tyrosyltRNA syntethase (YARS). This application is focused on the identification of molecular players and potential drug targets for this particular subtype of CMT. We will perform a screen for genetic modifiers of neurodegenerative phenotypes present in our recently generated Drosophila DI-CMTC model. The targeted genes will be selected based on their predicted abilities to interact with drug-like compounds. In this way, we will be able to gain original knowledge on DI-CMTC pathomechanisms and to translate it into a rational and reliable drug discovery program for this and possibly other inherited and acquired neuropathies.

Researcher(s)

• Promoter: Jordanova Albena
• Fellow: Ermanoska Biljana

Research team(s)

• Neurogenetics Group
• VIB CMN - Molecular Neurogenomics

Project type(s)

• Research Project