Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes degeneration of motor neurons, leading to skeletal muscle atrophy, paralysis and death. Mutations in Cu/Zn superoxide dismutase (SOD1) are one cause of ALS. Transgenic mice that express mutated SOD1 develop ALS similar to human disease. To determine the mechanism by which mutant SOD1 causes motor neuron degeneration, we will test three hypothesis: 1) ALS caused by different SOD1 mutations undergo different clinical and pathological progression; 2) mitochondrial damage precedes the onset of muscle weakness and accumulation of this damage leads to a dysfunction and deletion of normal mitochondria in motor neurons, culminating the onset of ALS; 3) oxidative stress plays a role in triggering the onset of ALS. To test the first hypothesis, we will investigate the pathological evolution in correlation with clinical progression in mice expressing G85R mutation and compare the findings with G37R and G93A mutants. We will delineate and compare the sequence of pathological events leading to motor neuron death in these three lines. By this approach, we will determine the differences and common characteristics of ALS caused by different SOD1 mutations. The outcome of this study will provide guidance to further elucidation of the disease mechanism and help to improve prognosis and design therapies tailored to different mutations. To test the second hypothesis, we will use electron microscopy to characterize the types of mitochondrial abnormality before and after onset of the disease. We will also determine the earliest time when mitochondrial abnormalities emerge and quantify the changes in the number of normal and abnormal mitochondria before and after the onset of the disease. To test the role of mitochondrial abnormality in triggering the onset of the disease, we will test whether energy supplementation by administering creatine delays the onset of the disease. To test the third hypothesis, we will measure the levels of oxidative markers at different disease stages to determine whether oxidative damage precedes or follows the onset of ALS. Further, we will test whether and how anti-oxidant treatment changes the course of disease progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035750-07
Application #
6351836
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Heemskerk, Jill E
Project Start
1996-04-01
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
7
Fiscal Year
2001
Total Cost
$333,246
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pharmacology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Ding, Hongliu; Schwarz, Dianne S; Keene, Alex et al. (2003) Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis. Aging Cell 2:209-17
Xia, Xu Gang; Zhou, Hongxia; Ding, Hongliu et al. (2003) An enhanced U6 promoter for synthesis of short hairpin RNA. Nucleic Acids Res 31:e100
Higgins, Cynthia M J; Jung, Cheolwha; Xu, Zuoshang (2003) ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neurosci 4:16
Jung, Cheolwha; Higgins, Cynthia M J; Xu, Zuoshang (2002) A quantitative histochemical assay for activities of mitochondrial electron transport chain complexes in mouse spinal cord sections. J Neurosci Methods 114:165-72
Higgins, Cynthia M J; Jung, Cheolwha; Ding, Hongliu et al. (2002) Mutant Cu, Zn superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J Neurosci 22:RC215
Zhang, Zaixiang; Casey, Diane M; Julien, Jean-Pierre et al. (2002) Normal dendritic arborization in spinal motoneurons requires neurofilament subunit L. J Comp Neurol 450:144-52
Jung, Cheolwha; Higgins, Cynthia M J; Xu, Zuoshang (2002) Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis. J Neurochem 83:535-45
Xu, Z; Tung, V W (2000) Overexpression of neurofilament subunit M accelerates axonal transport of neurofilaments. Brain Res 866:326-32
Kong, J; Xu, Z (1999) Peripheral axotomy slows motoneuron degeneration in a transgenic mouse line expressing mutant SOD1 G93A. J Comp Neurol 412:373-80
Kong, J; Xu, Z (1998) Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci 18:3241-50