The research in my laboratory studies the molecular basis of human aging with focus on the analysis of the cellular processes leading to the development of Werner syndrome (WS) and Hutchinson-Gilford Progeria syndrome (HGPS), two premature aging diseases. We also collaborate with the Reddy lab to study the molecular mechanisms of diseases caused by triplet repeat expansions.

The role of the Werner syndrome protein in the maintenance of cell homeostasis.

Werner Syndrome is an adult form of progeria that is characterized clinically by the premature appearance of cataracts, diabetes mellitus, neoplasia and atherosclerosis. The most common cause of death in WS individuals is myocardial infarction at the median age of 45 years. At the molecular level, cells from WS patients display a high degree of chromosomal deletions and rearrangements. The Werner syndrome protein (WRN) is a protein with exonuclease and helicase activities whose cellular function is poorly defined. Our studies have revealed a functional relationship between WRN and Ku70/80, a complex that is involved in the non-homologous end joining (NHEJ) DNA repair pathway as well as in chromosome ends (telomeres) maintenance. We have also determined that WRN depletion results in specific alterations in telomere length homeostasis. These findings suggest that WRN influences the processes that preserve chromosome ends, and we are using biochemical as well as genetic approaches to define the role of WRN in the processes.

Functional analysis of lamin A mutations causing Hutchinson-Gilford Progeria syndrome.

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature senescence. Affected children appear normal at birth, but within a year develop characteristic features of old age. The majority of HGPS children die from cardiac disease at an average age of 13 years. Genetic studies have identified a mutation in the lamin A/C gene in 18 classical HGPS cases. The mutation results in the production of a mutant lamin A protein with an internal deletion termed progerin. The mechanism by which expression of progerin leads to accelerated aging and cardiovascular disease is unknown. Lamin A is thought to be required for the maintenance of the nuclear structure and it has been proposed to influence nuclear processes such as gene transcription and DNA replication possibly through interaction with a set of yet to be identified cellular factors. We hypothesize that expression of the mutant lamin A (progerin) results in premature aging and cardiac disease as a consequence of the altered composition and function of lamin A-containing complexes within the nucleus. Current studies utilize biochemical and genetic approaches to identify proteins that are differentially associated to lamin and progerin and define the cellular processes deregulated by progerin expression.

Molecular basis of triplet repeat expansion and therapeutic approaches.

In collaboration with the laboratory of Dr. Reddy, we are testing the molecular etiology of the myotonic dystrophies DM1 and DM2 using biochemical approaches. An RNA dominant mechanism has been shown to underlie the development of several pathological features that are common to both DM1 and DM2. Specifically mutant RNAs encoding expanded CUG and CCUG repeat sequences are known to sequester the muscleblind family of proteins to form aberrant nuclear foci. In an ongoing series of experiments we are carrying out functional study of the muscleblind proteins and are attempting to decipher the protein profile of DM nuclear foci using molecular and biochemical approaches. We are also developing high throughput screens for small molecule therapy of triplet repeats expansion diseases.


Our work has defined several molecular mechanisms relevant for the biology of aging: We were one of the first two labs to report the identification of a physical and functional interaction between the Werner syndrome protein (WRN) and Ku70/80, a cellular factor linked to accelerated aging in mice (Li and Comai et al. JBC, 2000). We identified and functionally characterized a dynamic multiprotein WRN complex that influence telomere length homeostasis and demonstrated that WRN and Ku70/80 regulate the formation of pathological telomeric structures in human cells (Li et al. MCB, 2008). More recently, we uncovered an unanticipated function for WRN in the regulation of metabolic pathways that control macromolecule synthesis, energy production and the oxidative status of the cell (Li et al. Aging Cell 2014). Working on WRN has been challenging but fascinating, as it has enlightened us on the complex network of molecular interaction that regulate fundamental cellular processes controlling cell homeostasis. During our investigation of the molecular basis of HGPS, we demonstrated that the abnormal lamin A aggregates accumulating in cells expressing progerin are also present in cells from normal old-age individuals but absent in cells from young-age individuals (Candelario et al. Aging Cell, 2008). We further demonstrated that accumulation of prelamin A variants that are constitutively farnesylated induce the formation of lamin A aggregates and disrupt normal nuclear morphology, leading to changes in global gene transcription that severely inhibiting cell growth (Candelario et al. Exp. Cell Res., 2011). Collectively, these results demonstrate that prelamin A metabolism is a finely poised system and small perturbations in the normal pathway that produces mature lamin A can propel cells into a dysfunctional state that might affect healthy aging.