Hoppe, Thorsten - C 07

Inherited cerebellar ataxias are neurodegenerative diseases characterized by a progressive loss of Purkinje neurons. Cerebellar neurodegeneration results in a variety of symptoms, including decreased muscle control and incoordination, and clinical symptoms that often reflect the anatomical site of damage. Genetic studies identified disease-associated mutations in the ubiquitin ligase CHIP in more than 130 patients. The identified mutations have been linked to autosomal recessive spinocerebellar ataxia SCAR16 and autosomal dominant SCA48.

Recent experimental and clinical results suggest that CHIP has a protective role in preventing neurodegeneration. However, despite the neuroprotective activity in degrading aggregation-prone proteins, it is not yet clear how the nature and location of CHIP mutations contribute to the clinical expression of spinocerebellar ataxia and neuronal degeneration. Therefore, the main goal of our research is to understand the pathomechanism by which CHIP mutations cause spinocerebellar ataxia, which could contribute to the therapeutic treatment of neurodegenerative diseases. This proposal uses a multidisciplinary approach that combines protein biochemistry with C. elegans and cell culture approaches to investigate the role of CHIP in SCAR16 and SCA48. The goals of this proposal are to

1. characterize the structure-functional properties of disease-associated CHIP mutations;
2. explore the role of CHIP dimer formation on neuroprotection and organismal health;
3. identify CHIP-dependent substrates in a patient-derived human neuronal model.

Neurodegenerative diseases are incurable chronic neurological disorders whose risk increases with age and for which there are no treatments that modify the neurodegenerative process or provide neuroprotection, which is an increasingly important medical and public health issue as life expectancy increases. Understanding the neuroprotective role of the ubiquitin ligase CHIP will be of therapeutic importance for the treatment of numerous neurodegenerative diseases.

Our recent work identified that CHIP regulates the level of the insulin receptor, which is essential for metabolism and organismal health (Tawo et al., 2017). However, little is known about the neuroprotective activity of CHIP and its dysregulation in the context of neurodegenerative diseases. Therefore, the main goal of our research is to understand the pathomechanism by which CHIP mutations cause spinocerebellar ataxia, which could contribute to the therapeutic treatment of various neurodegenerative diseases. This proposal uses a multidisciplinary approach that combines protein biochemistry with C. elegans and cell culture approaches to investigate the role of CHIP in SCAR16 and SCA48. The goals of this proposal are to

• characterize the structural and functional properties of disease-associated CHIP mutations
• explore the role of the CHIP dimer-monomer transition on organismal health
• identify CHIP-dependent substrates in a patient-derived human neuronal model.

Tawo R., Pokrzywa W., Kevei E., Balaji V., Arian S., Höhfeld J.*, Hoppe T.* (2017) Cell 169: 470-482.

For more information, please check Hoppe Lab. 

• The Hoppe Lab
• CECAD Cologne
• CRC 1218: Ubiquitin-dependent coordination of mitochondrial-cytoplasmic quality control
• FOR 2743: Mechanical Stress Protection
• ProteoCure
• Humboldt Foundation
• European Molecular Biology Organization (EMBO)
• FOR 5504: Physiologiclal causes and consequences of genome instability
• CRC 1687: Systems-level consequences of fidelity changes in mRNA and protein biosynthesis
• SPP2453: Integration of mitochondria into the cellular proteostasis network