Neurodegeneration is a poorly understood biological phenomenon and an increasing public health challenge for our aging society. Discoveries of causal genetic mLitations have accelerated understanding the molecular mechanisms of these diseases. Mutations in Cu/Zn superoxide dismutase (SODI) have been linked to a subset of amyotrophic lateral sclerosis (ALS), a devastating motor neuron degenerative disease that leads to progressive paralysis. Understanding how a large number of S0D1 mutations, mostly single amino acid changes, cause the specific motor neuron degeneration may provide important insight into more prevalent sporadic ALS. To this end, we have developed novel SODI transgenic C. elegans and mice that exhibit neuronal dysfunction and locomotor defects. Protein;misfolding and aggregation, an increasingly common association with major neurodegenerative diseases, lare a main feature of both the invertebrate and the mammalian animal models. Initial characterization ofthe models traced the behavioral defects to synaptic dysfunctions. Here we propose to combine the use of the genetically tractable C. elegans and the mouse models to dissect the disease mechanism, including the role of protein aggregation. The elucidation may contribute to a better understanding of ALS as well as neurodegenerative diseases in general.

Public Health Relevance

Neurodegenerative diseases, including ALS, are an increasing public health challenge in our society. The project is aimed at understanding the basic cause ofione form of ALS. The results may have implication for neurodegenerative diseases in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
5R00NS062089-05
Application #
8197345
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gubitz, Amelie
Project Start
2009-04-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$243,784
Indirect Cost
$37,825
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218