Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. In some forms of ALS, protein misfolding and aggregation of specific proteins, including Cu/Zn superoxide dismutase (SOD1), have been implicated in motor neuron degeneration. Considerable advances in the understanding of neurodegenerative diseases, including ALS, have been made through studies involving genetically engineered mouse models. However, the complexity, time, and resources required for analyzing age-dependent neurodegeneration in mice limit the usefulness of mouse systems for large-scale genetic and chemical screens. To overcome these limitations, this laboratory has developed and validated a simpler invertebrate model of ALS in Caenorhabditis elegans, a fast- growing, transparent nematode that is amenable to molecular genetic analysis. This C. elegans model recapitulates the major features of human ALS, including a pronounced locomotor defect and the protein aggregation pathology in neurons. This model has made it possible to dissect the mechanism of SOD1-induced neurodegeneration in an efficient manner, using unbiased and large-scale genetic screens. These studies have led to the identification of genes that influence and modulate the neurodegeneration and protein aggregation in ALS disease models. The goal of the proposed project is to identify and elucidate the mechanisms through which ALS pathogenesis is influenced by these novel modifiers.
The specific aims are to identify and characterize key genes that influence and modulate the disease, to delineate the pathways through which the pathogenesis is influenced, and to extend the findings to related mammalian systems. The proposed studies, which combine mammalian systems with innovative and promising approaches using C. elegans, are expected to provide insight into fundamental mechanisms of neurodegeneration that may lead to novel approaches for treating ALS and related neurodegenerative diseases.

Public Health Relevance

The work in this proposal is aimed at elucidating the basic pathogenic mechanisms and the regulatory pathways involved in amyotrophic lateral sclerosis and related neurodegenerative diseases. Although these diseases are becoming an increasingly relevant public health challenge in our aging society, the mechanisms underlying most of these neurodegenerative conditions remain poorly understood. The molecular and genetic studies outlined in this proposal could lead to novel therapeutic interventions for those neurodegenerative diseases, including ALS, for which effective treatments are still lacking.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS074324-03
Application #
8449211
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gubitz, Amelie
Project Start
2011-08-15
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$311,574
Indirect Cost
$121,590
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Zhang, Tao; Wu, Yen-Ching; Mullane, Patrick et al. (2018) FUS Regulates Activity of MicroRNA-Mediated Gene Silencing. Mol Cell 69:787-801.e8
Nguyen, Dao K H; Thombre, Ravi; Wang, Jiou (2018) Autophagy as a common pathway in amyotrophic lateral sclerosis. Neurosci Lett :
Liu, Yang; Wang, Tao; Ji, Yon Ju et al. (2018) A C9orf72-CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress. Genes Dev 32:1380-1397
Zhong, Yongwang; Wang, Jiou; Henderson, Mark J et al. (2017) Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus. Elife 6:
Ji, Yon Ju; Ugolino, Janet; Brady, Nathan Ryan et al. (2017) Systemic deregulation of autophagy upon loss of ALS- and FTD-linked C9orf72. Autophagy 13:1254-1255
Hwang, Ho-Yon; Wang, Jiou (2017) Effect of mutation mechanisms on variant composition and distribution in Caenorhabditis elegans. PLoS Comput Biol 13:e1005369
Ugolino, Janet; Ji, Yon Ju; Conchina, Karen et al. (2016) Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling. PLoS Genet 12:e1006443
Wang, Jiou; Haeusler, Aaron R; Simko, Eric A J (2015) Emerging role of RNA‚ÄĘDNA hybrids in C9orf72-linked neurodegeneration. Cell Cycle 14:526-32
Zhang, Ke; Donnelly, Christopher J; Haeusler, Aaron R et al. (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525:56-61

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