Identifying therapeutic targets for Alzheimer's and Huntington's disease

The cellular dysfunction and resulting patholgies of Alzheimer's disease and Huntington's disease (as well as many other neurodegenerative diseases) are caused primarily by proteotoxicity, an accumulation of damaged or misfolded proteins. Evidence from work in the Kaeberlein lab and other labs suggests that proteotoxicity is a major contributor to aging.

Figure 1. Age-associate proteotoxicity

Many of the interventions that increase life span in animals do so by reducing age-associate proteotoxicity. It is our belief that these interventions may prove particularly useful for developing therapies to treat and prevent human diseases.

The first phase in our project to test potential therapies is to determine whether interventions that increase life span also delay disease onset in nematode models of Alzheimer's disease and Huntington's disease. These models were developed by the Morimoto and Link laboratories, and both show a rapid onset of adult paralysis due to decline in muscle cell function resulting from proteotoxicity (see movies of paralyzed worms here). In studies published in 2008 (Steinkraus et al., Aging Cell 2008), we reported that dietary restriction is a potent suppressor of disease progression in both the Alzheimer's disease and Huntington's disease models.

Currently, we are taking parallel approaches to identify leads that may be useful for treating proteotoxic diseases in people. The first is to determine the molecular mechanisms by which dietary restriction protects against proteotoxicity, with the intention to identify druggable targets or compounds that act via similar mechamisms. One pathway we are particularly excited about is the Target of Rapamycin (TOR) signaling pathway, which is thought to mediate many of the beneficial effects of dietary restriction. In unpublished studies, we have identified several TOR pathway components that suppress paralysis in both the Alzheimer's and Huntington's models. We have also observed protective effects from treating animals with the TOR-inhibitor rapamycin. Rapamycin (Sirolimus) is already used clinically for its immunosuppressive and anti-cancer properties and may prove of value for treating neurological diseases such as Alzheimer's and Huntington's disease.

The second approach we are taking is to identify potential avenues of treatment for proteotoxic disaese is to screen all of the genes and chemicals previously shown to influence longevity in C. elegans, and ask which also influence resistance to proteotoxicity in the Huntington's and Alzheimer's disease models described above. These studies are ongoing; however, to date we have identified several novel interventions that protect against proteotoxicity, including more than 30 genetic targets and two chemicals. A key goal of future efforts will be to determine which of these interventions is most likely to be a therapeutic value toward human diseases.

These efforts in the Kaeberlein lab have been supported by the following sources:

 

Proteotoxicity Screen of Longevity Genes

by Daniel Carr

Previous results in our lab have demonstrated that dietary restriction not only extends lifespan, but also suppresses progression of proteotoxicity disease systems, such as the Huntington's and Alzheimer's disease models. To test if the mechanisms that regulate longevity also regulate an organism's sensitivity to proteotoxicity, I have worked on a genetic screen on the above disease models in the nematode Caenorhabditis elegens. I reduced expression of genes previously shown to extend lifespan and assessed which of these influence the disease phenotype. Some significant genes of interest have surfaced from the screen, but further investigations are needed.