Davide Trotti, PhD
JHN 4th floor
Philadelphia, PA 19107
(215) 503-4358 fax
Research & Clinical Interests
Amyotrophic Lateral Sclerosis, Neurodegenerative diseases, Glutamate transporters and excitotoxicity, mitochondria ion channels and apoptosis
Research in my laboratory within the Weinberg Unit for ALS Research is focused on the study of molecular mechanisms of excitotoxicity leading to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). ALS is the most common adult motor neuron disease and its primary hallmark is the death of motor neurons of the spinal cord which leads to spasticity, hyper-reflexia, general weakness and muscle atrophy. Failure of respiratory muscles is generally the fatal event, occurring within 1-5 years of symptoms onset. Impairment in the glutamate transport system and loss of the glutamate transporter EAAT2 (a.k.a. GLT-1) are pathological events contributing to motor neuron death in ALS. We have accumulated expertise in the study of molecular mechanisms regulating the activity of glutamate transporters, their expression levels and post-translational modifications.
Another objective of our research is the study of mitochondria and the molecular mechanisms leading to their impaired physiology in ALS. Mitochondria are one of the main sources of energy production for the cells and play a pivotal role in maintaining neuronal cell alive. A pathology-driven impairment in these organelles may shift the balance between life and death and lead to neuronal degeneration.
We use a variety of biochemical, cellular and molecular biology techniques applied to primary cultures of astrocytes and motor neurons, embryonic stem cell-derived motor neurons and organotypic cultures isolated from transgenic mice and rats model of ALS. We also use electrophysiological techniques such as patch clamp, to study ionic conductances of the outer and inner membrane of mitochondria isolated from the spinal cord of transgenic mice model of ALS, and two-electrode voltage clamp to study the function of glutamate transporters expressed in cell lines and oocytes harvested from Xenopus laevis frogs.
The ultimate goal of our research is to unravel the molecular mechanisms of neurodegeneration in ALS and identify potential therapeutic targets that can be used in drug screening platforms for treating ALS.
Most Recent Peer-Reviewed Publications
- Mutation of the caspase-3 cleavage site in the astroglial glutamate transporter EAAT2 delays disease progression and extends lifespan in the SOD1-G93A mouse model of ALS
- Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene
- Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS/FTD
- Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P-Glycoprotein) in endothelial cells of the blood–brain barrier in mutant superoxide dismutase 1-linked amyotrophic lateral sclerosis
- Regulation of ABC efflux transporters at blood-brain barrier in health and neurological disorders
- ABC transporter-driven pharmacoresistance in Amyotrophic Lateral Sclerosis
- Role of mitochondria in mutant SOD1 linked amyotrophic lateral sclerosis
- Sumoylation of the astroglial glutamate transporter EAAT2 governs its intracellular compartmentalization
- Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate invitro and invivo neuronal death
- Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death
- Sumoylation of critical proteins in amyotrophic lateral sclerosis: Emerging pathways of pathogenesis
- Small peptides against the mutant SOD1/Bcl-2 toxic mitochondrial complex restore mitochondrial function and cell viability in mutant SOD1-mediated ALS
- Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS
- An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1
- Motor neuron impairment mediated by a sumoylated fragment of the glial glutamate transporter EAAT2
- Voltage-dependent inwardly rectifying potassium conductance in the outer membrane of neuronal mitochondria
- ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2
- Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis
- Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: Therapeutic implications for amyotrophic lateral sclerosis
- A caspase-3-cleaved fragment of the glial glutamate transporter EAAT2 is sumoylated and targeted to promyelocytic leukemia nuclear bodies in mutant SOD1-linked amyotrophic lateral sclerosis