Piera Pasinelli, PhD

Contact Dr. Pasinelli

900 Walnut St.
Suite 451F
Philadelphia, PA 19107

215-955-8394
215-503-9128 fax

How Do Motor Neurons Die in ALS?

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

Basic 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.

Drug screening:

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.

Publications

Most recent Peer-reviewed Publications

1. Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS
2. An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1
3. Motor neuron impairment mediated by a sumoylated fragment of the glial glutamate transporter EAAT2
4. In vivo and in vitro determination of cell death markers in neurons
5. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS
6. Voltage-dependent inwardly rectifying potassium conductance in the outer membrane of neuronal mitochondria
7. ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2
8. Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: Therapeutic implications for amyotrophic lateral sclerosis
9. 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
10. The proapoptotic BCL-2 family member BIM mediates motoneuron loss in a model of amyotrophic lateral sclerosis
11. Molecular biology of amyotrophic lateral sclerosis: Insights from genetics
12. Caspase-3 cleaves and inactivates the glutamate transporter EAAT2
13. Inhibition of SOD1 expression by mitomycin C is a non-specific consequence of cellular toxicity
14. Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria
15. Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice
16. Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter
17. RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells
18. Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity
19. Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: Associated mutations develop motor neuron disease
20. Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity

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