Loss of C9orf72 disrupts nucleoporins and contributes to TDP-43 mislocalization

Mutations in the C9ORF72 gene are the most common genetic cause of ALS. These mutations are unique in that unlike most other ALS-linked genes, where there is often a mistake in a single piece of DNA, C9ORF72 mutations involve a section of DNA that is abnormally repeated, often hundreds or even thousands of times. These repeat mutations result in less of the normal C9ORF72 protein being produced within cells, which is suggested to impair its ability to do its normal job.

Growing evidence also points to a significant involvement of C9OF72 mutations in the disruption of nucleocytoplasmic transport (NCT) within cells. NCT involves the exchange of substances between two important compartments of the cell, the nucleus and cytoplasm, and is crucial to cell survival. The exact mechanism for this disruption, however, is still unknown.

With this award, Dr. Philip McGoldrick will explore the link between a loss of normal C9ORF72 function and nucleocytoplasmic transport, and whether dysfunction in this system contributes to the abnormal behaviour of another ALS-linked protein, called TDP-43, which is found to be mislocalized from the nucleus to the cytoplasm in 97% of all ALS cases. To date, most of the connections made between C9ORF72 mutations and NCT have related to a different mechanism, making Dr. McGoldrick’s work unique in the field.

Expanding on previous work, Dr. McGoldrick will study changes in the biology of nuclear pore complexes (NPCs), the large protein complexes responsible for moving substances between the nucleus and cytoplasm, as well as the downstream effects of these changes on important cellular processes such as the stress response and protein homeostasis. He will also evaluate whether loss of C9ORF72 in combination with normal ageing processes contributes to neuronal degeneration in human cell models.

Ultimately, this work will help researchers to better understand how an important cellular process may be disrupted in the early stages of ALS. Understanding why these changes occur and what the downstream effects are will no doubt be key to future therapeutic development. Dr. McGoldrick hopes to grow this project into a career based on developing new laboratory models and treatments for all forms of ALS.