Scientific Interests
- The regulation of aging at the genetic, cell biological and organismal levels.
- Protein folding, aggregation and deposition within the single cell.
- Mechanisms and biological activities that link aging and toxic protein aggregation.
- Aging manipulation as a strategy to combat neurodegenerative disorders.
Aberrant protein aggregation is linked to the development of various late-onset human neurodegenerative disorders, such as Alzheimer and Parkinson diseases. Interestingly different neurodegenerative disorders share surprisingly similar temporal emergence patterns: familial, mutation-linked cases onset during the fifth decade of life while sporadic cases do not emerge earlier than the seventh decade. This common emergence pattern defines aging as the major risk factor for the development of these maladies. Why neurodegenerative disorders onset late in life and why distinct diseases share similar temporal patterns are principal enigmas that are studied in our laboratory. To explore the mechanistic links between aging and toxic protein aggregation we use the nematode Caenorhabditis elegans (C. elegns) and mammalian cell cultures. The Insulin/IGF signaling pathway (IIS) is a prominent aging and lifespan regulator. In C. elegans, IIS reduction results in slowed aging, extended lifespan and elevated stress resistance. Recently we discovered that IIS reduction can also protect worms from toxic aggregation of the human Alzheimer disease associated peptide, A. The IIS mediates this protection by regulating two opposing activities, disaggregation and protective hyper-aggregation. In the laboratory we study in details the mechanisms that link aging and toxic protein aggregation via the IIS and other aging regulating pathways. We also characterize the cell biological mechanisms that act to detoxify protein aggregates at the single cell level. Our long term goal is to develop therapies that will enable to maintain the activity of the mechanisms that protect the young organism from late-onset disorders through late stages of life aiming to promote healthy aging.
The Biological Systems
The major model organism used in the lab is the nematode C. elegans. These worms have remarkable advantages for the research of aging and toxic protein aggregation. C. elegans live very short life (wild-type worm lives on average only 19 days) yet, the known aging regulating pathways are highly conserved from worms to mammals. The worms are post-mitotic, just like neurons, and the lineage of each and every cell is known. It is relatively easy to create transgenic worms and to cross different strains. Biochemistry techniques are also applicable as worm can be easily homogenized to test protein content or perform protein-protein interaction assays. The worms are transparent, thus, immuno-fluorescence and the tracking of fluorescently tagged proteins are easy to perform. But most important is the ease to silence genes using RNAi. The expression of a target gene can be drastically reduced simply by feeding the nematodes with bacteria expressing the RNAi construct towards the target gene.
A worm carrying GFP tagged DAF-16.
Worm expressing RFP under gtr-1p and GFP under gcy-8p
A cell containing an aggresome.
Despite the overwhelming advantages of C. elegans as a model system, some research aspects such as protein trafficking, need to be validated in mammalian systems. In our laboratory we utilize mammalian cell cultures to support the observations obtained in the worms using various microscopic and biochemical techniques. In addition, we have a colony of Alzheimer's model mice that we utilize to test whether our findings are conserved from worms to mammals.
