EducationB.S., University of Catania (Italy), 1999
Ph.D., University of California-Irvine, 2005
ResearchThe elderly population is the fastest growing element of our society, hence understanding the factors that contribute to cognitive decline is imperative, particularly as age is the major risk factor for several neurological disorders. If nothing is done to alter the current course, the number of people suffering from age-dependent neurological disorders will increase substantially, which will exacerbate the already high socio-economical impact these diseases exert on our society.
Overall, we use broad genetic approaches to modify the genome of animals with the goal of understanding the role of specific neuronal populations and for elucidating the molecular mechanisms underlying age-dependent neurodegenerative disorders, such as Alzheimer's disease and Frontotemporal dementia. These genetic approaches include direct manipulation of the mouse genome through the development of inducible transgenic mice and viral transduction mechanisms. Both of these approaches offer precise temporal control and regional specificity and can be superimposed with varying developmental stages of the CNS. The outcome of these studies will reveal critical molecular determinants underlying motor and cognitive dysfunction in the mammalian CNS.
Particularly, we focus on two main areas of research:
UNDERSTANDING THE MOLECULAR MECHANISMS UNDERLYING THE EARLY COGNITIVE DEFICIT IN ALZHEIMER'S DISEASE.
Alzheimer's disease (AD) is the most common neurodegenerative disorder. The two hallmark lesions of AD are amyloid plaques, formed of a small peptide called Aß, and neurofibrillary tangles, mainly composed of the hyperphosphorylated protein tau. Compelling evidence indicates that Aß plays a pivotal role in the cognitive decline in AD. However, the molecular mechanisms underlying such phenomenon are largely unknown. The overall goal of my laboratory is to elucidate the molecular and cellular basis of cognitive decline in AD. Although neuronal loss is a major feature of AD, the extent to which behavioral alterations directly relate to neuronal loss is debatable. For example, patients show astonishing fluctuations in brain functions during disease progression. Such sudden variations are unlikely to be caused by rapid changes in cell numbers, but are most likely due to complex compensatory mechanisms of signaling pathways, neuronal activities and network interactions. This suggests that some behavioral changes associated with AD could be due to alterations in neuronal activities and networking. To better understand these mechanisms, currently we are focusing on signaling pathways that are essential for learning and memory. Specifically, we are investigating the involvement of the mammalian target of rapamycin, a protein kinase that plays a key role in maintaining protein homeostasis, in AD pathogenesis. Concurrently, we are developing genetic and systems approaches to elucidate how unaffected systems compensate for the neuronal loss of affected brain regions. These compensatory mechanisms represent a built-in system that the brain evolved to reduce functional consequences after neuronal injury. Thus, enhancing these compensatory mechanisms may slow down the rate of cognitive decline in patients. Understanding this phenomenon can lead to the discovery of a whole new area of study and the identification of new therapeutic targets. Understanding this phenomenon can lead to the discovery of a whole new area of study and the identification of new therapeutic targets.
UNDERSTANDING THE MOLECULAR PATHWAYS UNDERLYING FRONTOTEMPORAL LOBAR DEGENERATION.
Frontotemporal lobar degeneration (FTLD) is the second most common form of dementia in people under the age of 65. The majority of FTLD cases, caused by loss-of-function mutations in the gene encoding the growth factor progranulin (PGRN), are characterized by the accumulation of transactive response DNA-binding protein 43 (TDP-43) and are referred to as FTLD-TDP. However, how do loss-of-function mutations in PGRN lead to TDP-43 accumulation remains a major unresolved question in the field. In FTLD-TDP, TDP-43 is mislocalized from its nuclear location to the cytoplasm, where it accumulates and is proteolytically cleaved to form C-terminal fragments. Although the ~25kDa C-terminal fragment of TDP-43 (herein referred to as TDP-25) selectively accumulates in affected brain regions, its role in the disease pathogenesis remains to be established. Further, recent evidence is converging on oxidative damage as another feature of FTLD-TDP and other neurodegenerative disorders characterized by TDP-43 accumulation, such as amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder sharing overlapping features with FTLD-TDP. Whether oxidative damage contributes or is a consequence of TDP-43 accumulation remains elusive.
To elucidate the role of TDP-25 in FTLD-TDP, we generated a novel transgenic mouse by expressing TDP-25 in neurons. These mice mimic several aspects of FTLD-TDP including age-dependent increase in TDP-25 levels, oxidative damage, reduction of endogenous nuclear TDP-43 levels, and cognitive dysfunction. Furthermore, we and others have shown that autophagy plays a key role in TDP-43 metabolism. Here we provide preliminary evidence showing that autophagy is decreased in PGRN knockout (PGRNko/ko) mice and that this reduction correlates with a decrease in p62 levels, a protein that accumulates in FTLD-TDP brains and regulates autophagy induction. The overall goal of this project is to identify the molecular link between PGRN and TDP-43. Our data make the autophagic system a good candidate to link the lack of progranulin with the accumulation of TDP-43. We use multidisciplinary approaches that allow us to identify the mechanistic links between PGRN and TDP-43 accumulation, and the molecular basis of cognitive decline in FTLD-TDP.
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