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Protein Trafficking to the Liposomes is Abnormal in Huntingdon Disease

Huntingdon disease is a hereditary neurodegenerative disease that progressively and specifically destroys the cerebral cortex and basal ganglia, where the most affected cells are the neurons of the corpus striatum. This disease presents between the ages of 30 and 50 years and is characterized by cognitive and motor disorders. The most characteristic trait is exaggerated movement of the limbs, which lead to completely incapacitating behavior by the patient.

The disease is caused by a mutation of the huntingtin protein, which is widely distributed throughout the cells. Huntingtin is located in the Golgi apparatus and in the transport vesicles. It interacts with intracellular motors and allows movement of the vesicles within the cell. The mutation of the protein consists of an abnormal increase of more than 35 repetitions of glutamine at the N-terminal. The molecular mechanisms that lead this mutation of huntingtin to cause neuron dysfunction and death, particularly in neurons of the corpus striatum are not understood.

A UB-IDIBAPS team led by Dr. Josep Maria Canals and Dr. Jordi Alberch of the department of Cell Biology, Immunology and Neuroscience of the Faculty of Medicine, has been focusing its research in this area for some time. The latest study by this team, published in Molecular Biology of the Cell with Daniel del Toro as the first author, shows that the huntingtin mutation affects the lysosomal pathway. Previous studies showed that the protein played a role in the traffic of vesicles from the Golgi apparatus ( The Journal of Neuroscience, 2006).

The new results show that when huntingtin is mutated, its levels fall in the Golgi apparatus. There is also a reduction in the levels of another protein, optineurin, impeding the formation of a complex on which the secretory pathway depends. Clathrin-regulated release of proteins from the Golgi apparatus is thereby affected and the transport vesicles accumulate around the apparatus. The iFRAP technique was used to view the process; this consists of marking the proteins with fluorescent markers and following their secretion in real time from the Golgi apparatus using confocal microscopy.

The principal novelty of the research lies in the fact that mutated huntingtin affects not only protein trafficking to the plasma membrane but also to the lysosomal pathway. This dysfunction means that the lysosomes do not receive the enzymes necessary for carrying out the degradation processes, thereby causing an increase in autophagic vesicles. Future research by this team will explore the role of huntingtin in disorders of the lipid pathways and of cholesterol, which are also affected in Huntington disease.