Identifying Common Mechanisms of Neurodegeneration in Alzheimer's Disease, Amyotrophic lateral sclerosis and Parkinson's Disease

This project is to support the initiation of a collaboration between the NEURONODE consortium, led by Dr. McCormick at Queen Mary University of London, and Dr. Finkbeiner's lab at the Gladstone Institute in San Francisco. Both groups propose to identify common mechanisms in neurodegenerative diseases. The collaboration with involved the exchange of models, methods, investigational tools, and expertise. This exchange will aid both groups in achieving their goals. We will expand our analysis to identify disease mechanisms involved neurodegeneration in AD and better understand if how the stress response of cells contribute to common pathogenic processes in the different diseases. They will provide critical information on how changes in protein translation may affect protein turnover in disease. Our joint studies will provide insights on the role of the cell degradation pathways and the cell trafficking pathways in neurodegenerative diseases.

This application is to support collaborative studies between Dr. Finkbeiner's lab and the JPND NEURONODE consortium. Both groups propose to identify common mechanisms in neurodegenerative diseases.
We propose to begin a collaboration with Dr. Finkbeiner's lab and extend our studies into Alzheimer's disease (AD). NEURONODE are conducting studies on disease models (AD-PSEN1 L235P; ALS: C9orf72; PD: PARK2 ex1 del.) that are different from those of Dr. Finkbeiner's. We will provide these models to Dr. Finkbeiner's lab and determine if autophagy is impaired across different neurodegenerative diseases. The studies will be an analysis of changes in mitochondria (Mt) turnover, which will complement studies by NEURONODE to evaluate metabolite changes related to neurodegeneration.

We also propose pilot studies on the role of stress granules (SGs) in neurodegeneration. SGs contain RNA-binding proteins, such as TDP43, a protein implicated in pathophysiology of AD, ALS, and FTD. TDP43 translocates to the cytoplasm from the nucleus in response to stress and associates with core SG proteins. Disease-causing TDP43 mutations slow the kinetics of SG resolution, and persistent SGs are associated with the misfolding of TDP43 and the formation of insoluble deposits in neurodegenerative diseases.

Dr. Finkbeiner's group will provide the disease models they are using. We will investigate if translational control mechanisms are impaired in human disease models and study more in depth the structural make up and function of the SGs. This will allow us to relate our pathway analysis to the US lab models.

The exchange of models, methods, investigational tools, and expertise will aid both groups in achieving their goals. We will expand our analysis to identify disease mechanisms involved neurodegeneration in AD and better understand if SGs contribute to common pathogenic processes in the different diseases.

This application is to support collaborative studies between Dr. Finkbeiner's lab and the JPND NEURONODE consortium. Both groups propose to identify common mechanisms in neurodegenerative diseases.

The primary beneficiaries of this research will be those patients suffering from neurodegenerative diseases (NDs). This pioneering collaboration will provide novel and insightful information on new mechanisms of NDs that can serve as potential biomarkers and developments for future drug therapies. The second major population will be researchers in the area of NDs. They will have access to novel information not before available on how these NDs develop. The third group of people will be the young researchers involved with the collaboration. These researchers will be exposed to an international collaboration involving five countries with a vast array of data.