Rudolf Magnus Institute for Neurosciences-Utrecht University-Utrecht, The Nethrelands
Post-doctoral fellowship - Massachusetts General Hospital-Harvard Medical School, Boston, MA
Associate Professor (2006)
Research and Clinical Interests
Research in Dr. Pasinelli's laboratory in the Weinberg Unit for ALS Research focuses on the study of the cellular and molecular events that lead to motor neuron death in Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's disease.
ALS is a typical neurodegenerative disease caused by degeneration and death of motor neurons in the spinal cord, brain stem and motor cortex. This leads to muscular atrophy. Death occurs 3 to 5 years from onset. Currently there is no cure for ALS.
The work done in the laboratory focuses on the molecular mechanisms of motor neuron degeneration caused by two ALS-associated proteins. Disease causative mutations in these proteins cause them to undergo conformational modifications and mislocalize within the cells. The goal is to understand the correlation between toxicity and mislocalization and to identify the molecular targets of these mislocalized proteins once they reach the cellular compartment were they do not normally reside. The ultimate goal is to identify potential therapeutic targets. To this end, work in the laboratory develops in two components: (1) Basic research and (2) Translational research.
Basic research: Mitochondria abnormalities are a characteristic feature of ALS and mitochondria are a primary target of toxicity of disease-causative mutations. Our research aims at understanding the molecular mechanisms underlying mitochondria dysfunction in ALS. We use neuronal cell cultures and transgenic ALS mice in which we study mitochondria defects using a variety of biochemical, cell- molecular biology and imaging techniques.
Translational research: What we learn from our basic research gets translated into the development of cell-based assays to screen for therapeutics. We have developed two cell-based assays that recapitulate aspects of cell dysfunction in ALS and adapted them for moderate high-throughput (96 or 384 wells) drug screening.
A second component of our translational research involves the phenomenon of pharmacoresistance in ALS. We study how high expression and high transport efficiency of the multi-drug resistance transporter P-glycoprotein negatively affects drug delivery and ultimately drug efficacy in the mouse model of ALS.