Aging
Aging of the brain decreases cognitive and motor abilities and leads to morphological and functional changes of certain populations of neurons. These changes increase risk towards neurodegenerative diseases such as Parkinson’s or Alzheimer’s disease and are believed to contribute to neurodegeneration and aging.
Aging is the major risk factor for the development of neurodegenerative disorders. To date, only few studies have addressed the molecular and biochemical mechanisms underlying aging in postmitotic differentiated neurons. Research of aging has focused on model systems (yeast, round worm, fruit fly) and proliferating cells (replicative senescent). Impairment in protein turnover, calcium metabolism, increased production of reactive oxidative species, and instability of mitochondrial and nuclear genome are some of the changes that have been characterized. Using a newly established in vitro model of aged, differentiated, postmitotic neurons we will study the transcriptional regulation of aging by DNA microarrays. In addition we will study the transcriptional regulation of aging in different brain areas. Subsequently we will study the functional role of the regulated transcripts in the aging process. These studies will lead to a new understanding of the mechanisms underlying aging and neurodegenerative disorders.
Neuroprotection
The ultimate aim of our research on the pathogenesis of neurodegenerative diseases is to develop treatments that interfere with its deleterious cascade. This would add to the treatments that are available today, namely dopamimetics and deep brain stimulation, and also enhance the prognosis and the quality of life of patients. We and others have identified protein aggregates, oxidative stress and mitochondrial dysfunction, excitotoxicity and apoptosis as important mediators of neuronal death, specifically in Parkinson’s disease
Gene Therapy
In most gene therapy studies, a “normal” gene is inserted into the genome to replace an “abnormal” disease-causing gene. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient’s target cells. Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA. Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists have tried to take advantage of this capability and manipulate the virus genome to remove disease-causing genes and insert therapeutic genes.
Due to the very efficient nuclear entry mechanism of adenovirus and its low pathogenicity for humans, adenovirus-based vectors have become gene delivery vehicles that we are using to infect primary cell culture of neurons, for example. The adenoviral vectors system (AdEASY), used in our lab, allows the production of recombinant adenoviruses with high titers, including a reporter gene for monitoring the infection efficacy.
Lentiviral vectors provide attractive gene delivery vehicles in the context of non-dividing cells. The vectors also have proved to be highly efficient for in vivo gene delivery and achieve stable long-term expression of transgene in serveral target tissues, such as the brain.
A third-generation lentivirus vector was designed to improve their biosafety.