Limited drug penetration is an obstacle that is often encountered in the treatment of CNS diseases. One mechanism that may contribute to this phenomenon is the expression of ATP-binding cassette (ABC) drug efflux transporters (i.e. P-glycoprotein or P-gp, Multi-drug resistance proteins or MRPs, breast cancer resistance protein or BCRP, a.k.a. ABCG2) at the blood brain barrier (BBB) and blood cerebrospinal fluid (BCSF) barrier. ABC transporters also localize to a lesser extent at the CNS parenchyma cells where they act as secondary barrier to neural penetration of substances. Efflux transporters also extrude catabolites and toxins to prevent their harmful accumulation in the cell, constituting the major mechanism of cell adaptation to disease-mediated and environmental stress. Little is known on ABC transporters localization and regulation in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of the motor system. Our preliminary data show increased P-gp expression in spinal cord astrocytes of the SOD1-G93A mouse model of ALS as well as in spinal cord specimen homogenates of sporadic and familial ALS patients. From a therapeutic perspective, this suggests that the obstacle to drug penetration in the CNS is increased by the disease and must be overcome to develop effective pharmacotherapies for ALS. Given their multi-specificity, the recognition of efflux transporters as critical players in CNS diseases is unquestioned although important questions remain unanswered. For example: How does ALS affect efflux transporters localization and function? Which ALS-specific signaling pathways are responsible for up-regulation in P-gp? Will ALS-mediated up-regulation in P-gp and/or other ABC transporters change how we therapeutically treat the mouse model of the disease, and ultimately ALS patients? To fill this gap in knowledge, we propose: (1) To investigate activity, expression and distribution profile of P- gp and other relevant ABC drug transporters in ALS;(2) To study whether efflux transporter activity in non- neuronal cells contributes to motor neuron degeneration in in-vitro and in-vivo models of ALS;(3) To investigate the impact of eliminating ABC transporter function on ALS therapeutics.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is one of the most devastating and lethal progressive neuromuscular disorders, affecting motor neurons in the spinal cord and motor cortex. Over 30,000 people are living with this disease in the United States and approximately 5,000 Americans will be diagnosed with ALS this year. Multidrug efflux ABC transporters limit the entry into the brain and spinal cord of a large number of drugs, contributing to the poor success rate of promising drug candidates, and regulate the extrusion of a variety of substances, including catabolites and potential toxic molecules that could be harmful to cells. Modulating the activity and expression pattern of these transporters could therefore improve drug delivery into the brain and spinal cord and affect the overall cellular homeostasis. In this application we propose to study the regulation and role of these ABC transporters in ALS. Our ultimate goal is to understand the pathogenic mechanisms of ALS to improve the chances of success of pharmacotherapy for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS074886-04
Application #
8600333
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Gubitz, Amelie
Project Start
2011-03-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$305,156
Indirect Cost
$108,281
Name
Thomas Jefferson University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Jablonski, Michael; Miller, David S; Pasinelli, Piera et al. (2015) ABC transporter-driven pharmacoresistance in Amyotrophic Lateral Sclerosis. Brain Res 1607:14-Jan
Jablonski, Michael R; Jacob, Dena A; Campos, Christopher et al. (2012) Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS. Neurobiol Dis 47:194-200