University of California, San Diego (UCSD)

Axonal Transport Deficits and Therapeutic Avenues in Alzheimer’s Disease

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The Roy lab investigates transport and trafficking within neurons and its disruption in neurodegenerative diseases including Alzheimer’s and Parkinson’s disease. A common theme in neurodegenerative diseases is the dysfunctions of synapses in the brain. Synapses are communicating “outposts” in the brain that are responsible for transmitting information and allowing the brain circuitry to function normally. There is an abundance of data showing that synaptic damage is a very early pathology responsible for the vast majority of neurological anomalies seen in neurodegenerative diseases and dementia. For proper functioning, synapses need to be continuously supplied with new “raw materials” that are synthesized in cell bodies that are typically very distant from the synapses. These raw materials are continuously delivered into synapses via cargo-trafficking, much like trucks delivering food out to grocery stores.

Our overall hypothesis is that in neurodegenerative diseases, disturbances in cargo-trafficking leads to defects in the functioning of synapses within the brain that eventually lead to their dysfunction and disease symptoms in the human brain(1) Using the above analogy, in these neurodegenerative diseases, our stores don’t have any food. We have recently shown that such cargo-trafficking deficits are critical in leading to the synaptic pathology caused by alpha-synuclein, a protein prominently involved in both Parkinson’s and Alzheimer’s disease, and we think that such “destructive trafficking cascades” are eventually responsible for neurodegeneration and dementia in these diseases(2). Besides investigating these destructive cascades that will give insights into the precise pathways that need to be targeted for therapy, over the next few years we hope to launch a highly focused drug discovery program that will rationally interfere with these destructive cascades.

(1) Axonal transport defects as a common theme in neurodegenerative diseases.
Subhojit Roy, Bin Zhang, Virginia M.-Y. Lee and John Q. Trojanowski. Acta Neuropathologica Jan 2005; 109(1):5-13.

(2). A pathologic cascade leading to synaptic dysfunction in α-synuclein-induced neurodegeneration (2010). David Scott, Iustin Tabarean, Yong Tang, Anna Cartier, Eliezer Masliah and Subhojit Roy. Journal of Neuroscience 2010 Jun16;30(24):8083-95.