Piera Pasinelli, PhD
JHN 4th floor
Philadelphia, PA 19107
(215) 503-4358 fax
Research and Clinical Interests
Neurodegenerative diseases, Amyotrophic Lateral Sclerosis
Research in the laboratory 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 we do in the laboratory focuses on one particular form of the disease: familial ALS caused by mutations in the gene encoding for the cytosolic copper-zinc superoxide dismutase (SOD1). We study the molecular mechanism(s) by which mutated SOD1 (mutSOD1) causes motor neuron degeneration. The ultimate goal is to identify potential therapeutic targets.
To this end, work in the laboratory develops in two components:
1. Basic research
2. Drug screening or translational research
Mutations in SOD1 cause motor neuron death through gain of toxic properties that are not fully delineated. This toxicity impairs multiple cellular functions. Mitochondrial abnormalities and activation of cell death genes are characteristic features of mutSOD1-mediated ALS. Our basic research program studies: a) the molecular switches that, upon mutation, convert SOD1 (normally a pro-survival protein) into a toxic molecule using in vitro biochemical approaches,
b) the pathological mechanisms governing mutSOD1-mediated cell death and mitochondrial dysfunction in neuronal cultures and transgenic animal models.
What we learn from our basic research gets translated into the development of cell based assays to screen for therapeutics. The goal is to develop drugs to cure or ameliorate the disease.
We use different techniques from basic molecular biology to biochemistry and cell biology. We use cloning, protein electrophoresis, immunoblotting, immunofluorescence and immunoprecipitation techniques, in vitro affinity binding assays and subcellular fractionation to isolate organelles from the spinal cord of ALS mice.
As model systems we use neuronal cell cultures with mutSOD1 and transgenic ALS mice that express the human-mutated SOD1 gene. These mice develop and ALS-like disorder; we follow pathogenic molecular changes in the motor neurons of these mice as disease progresses.
Most Recent Peer-Reviewed Publications
- Blood–Brain Barrier Driven Pharmacoresistance in Amyotrophic Lateral Sclerosis and Challenges for Effective Drug Therapies
- 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
- Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity
- Regulation of ABC efflux transporters at blood-brain barrier in health and neurological disorders
- ABC transporter-driven pharmacoresistance in Amyotrophic Lateral Sclerosis
- Inhibiting drug efflux transporters improves efficacy of ALS therapeutics
- 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 in vitro and in vivo neuronal death
- Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate invitro and invivo neuronal death
- Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS
- 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
- In vivo and in vitro determination of cell death markers in neurons
- Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS