Danny Hatters
Aberrant protein conformations, cellular toxicity and disease
Research in our laboratory focuses on how misfolded protein conformations cause cellular dysfunction and neurodegenerative disease. We are interested in studying how the aberrant conformations of huntingtin, the protein associated with Huntington’s disease, interfere with the cellular machinery. A second area of investigation in collaboration with Andy Hill’s lab is how the aberrant infectious conformation of the prion protein, which is associated with Creutzfeldt-Jakob disease, movess within and between cells. Huntington’s disease is one of the most common inherited neurodegenerative diseases. The disease is caused by an abnormally long polyglutamine repeat length near the amino-terminus of huntingtin. Normal alleles of the gene encoding huntingtin have up to about 36 continuous glutamines, while disease-causing alleles have more than 36 glutamines in this repeat. The extra glutamines cause the protein to change conformation, aggregate and form inclusions in neurons. However, it is not clear exactly how this process is associated with neuronal death and disease.
Abnormal protein conformations in the cellular environment. Are monomers, oligomers or aggregates toxic? How do they influence the cellular machinery? What is their temporal and spatial localization?
Current questions:
- Why are altered conformations of huntingtin toxic?
- How do misfolded huntingtin conformations interfere with the cellular machinery?
- How does the length of polyglutamine affect the conformation of huntingtin?
- How are pathogenic prion proteins moved in and out of cells?
- Where do different conformations of huntingtin and the prion protein accumulate in the cell?
Approaches:
We use a number of biophysical, biochemical and cellular tools to tackle these questions:
- Biophysical techniques such as circular dichroism and fluorescence spectroscopies, analytical ultracentrifugation, and gel filtration chromatography for probing purified huntingtin conformations
- Site-directed mutagenesis and protein engineering to investigate how structural properties of huntingtin and the prion protein influence cellular machinery
- Expression of huntingtin and prion proteins in mammalian cells for visualisation by fluorescence microscopy and immunostaining.
Lab personnel
HeadDr Danny HattersResearch staffYasmin Mohamed Ramdzan (Research Assistant)Graduate studentsSevgi Irtegun Honours studentsMaya Olshina |