Amyotrophic lateral sclerosis (ALS) results from the progressive degeneration of motor neurons. Astrocytes are important for neuronal function and survival, but exactly how astrocytes contribute to ALS pathogenesis is not known. Compared to neurons, astrocytes can be replaced much more easily and thus are the focus of regenerative medicine. Familial ALS is caused by pathogenic mutation in individual genes, including TDP-43. A critical need in ALS research is determining how astrocytes contribute to the initiation and progression of motor neuron degeneration in the presence and absence of the disease gene in astrocytes. Using a tetracycline- inducible gene expression system, we have created transgenic rats that restrictedly and reversibly express mutant TDP-43 in astrocytes. By microarray assays, we have determined the expression profiles of astrocytic genes. Many secretory genes are induced in astrocytes expressing mutant TDP-43. Functional analyses of astrocytic genes suggest a loss of neuroprotective functions and a gain of neurotoxic properties in astrocytes expressing mutant TDP-43. Here we will further determine how mutant TDP-43 in astrocytes causes non-cell- autonomous motor neuron death in transgenic rats. In response to neurodegeneration, astrocytes become reactive and may play important roles in disease pathogenesis. Increasing evidence strongly suggests that reactive astrocytes gain neurotoxic properties, but how reactive astrocytes execute neurotoxicity remains to be determined. Using various approaches, we have identified an inducible gene that is secreted by reactivate astrocytes. We will further define the route by which reactive astrocytes use to promote neurodegeneration. This proposal will determine how astrocytes contribute to the initiation and progression of motor neuron death in the presence and absence of mutant TDP-43 in astrocytes, advancing our understanding of ALS disease mechanisms.

Public Health Relevance

Using various approaches and complementary model systems, this proposal will dissect disease mechanisms underlying neurodegeneration in amyotrophic lateral sclerosis and thus will guide the development of therapies for this devastating disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS084089-02
Application #
8653631
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Tieu, Kim; Xia, Xu-Gang (2014) Cytosolic PINK1 escapes from mitochondria to promote dendritic outgrowth. J Neurochem 128:787-9
Huang, Cao; Huang, Bo; Bi, Fangfang et al. (2014) Profiling the genes affected by pathogenic TDP-43 in astrocytes. J Neurochem 129:932-9
Tong, Jianbin; Huang, Cao; Bi, Fangfang et al. (2013) Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats. EMBO J 32:1917-26