Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the most common motor neuron disease. ALS is clinically characterized by the degeneration of motor neurons in the brain and spinal cord, culminating in paralysis and death within 1-5 years. Presently, there is no cure for ALS. Mutations in the gene encoding superoxide dismutase (SOD1) cause familial, or inheritable, ALS (FALS). FALS constitutes 10% of ALS cases, whereas the remaining 90% are sporadic in nature (SALS). Although SALS and FALS are clinically indistinguishable, the causative factor(s) associated with SALS are unknown. More than 150 mutations in the SOD1 gene have been linked to FALS, and yet it is still undetermined whether the wild-type (WT) form of SOD1 plays a role in sporadic ALS. The overall goal of this proposal is to test the hypothesis that altered modifications of SOD1 WT are implicated as causative factors in SALS. We have designed our experimental approach to address four criteria that in our view must be fulfilled to define a causal role for SOD1 WT in SALS: detection of modified SOD1 WT in SALS specimens (Aims 1, 2 and 3);relevance of modified SOD1 WT to pathogenic pathways in the disease (Aims 4 and 5);an appropriate dose response relationship between modified SOD1 WT and severity of disease (Aims 2 and 5);and demonstration that modified SOD1 WT can propagate the disease in normal hosts or cells (Aim 5). These experiments have the potential to significantly impact ALS research, by defining disease mechanisms and by identifying therapeutic targets.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the most common motor neuron disease. While 10% of ALS cases are familial or inherited, the vast majority (90%) are sporadic (SALS). Mutations in superoxide dismutase (SOD1) have been identified as the most common cause of FALS. However, the origins of SALS have not been identified, nor is it known if wild-type (WT) SOD1 is involved in SALS. The goal of this proposal is to further test the hypothesis that altered modifications of WT SOD1 are implicated as causative factors in SALS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067206-03
Application #
8248066
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gubitz, Amelie
Project Start
2010-07-15
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$352,647
Indirect Cost
$138,272
Name
University of Massachusetts Medical School Worcester
Department
Neurology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Boopathy, Sivakumar; Silvas, Tania V; Tischbein, Maeve et al. (2015) Structural basis for mutation-induced destabilization of profilin 1 in ALS. Proc Natl Acad Sci U S A 112:7984-9
Ward, C L; Boggio, K J; Johnson, B N et al. (2014) A loss of FUS/TLS function leads to impaired cellular proliferation. Cell Death Dis 5:e1572
Sama, Reddy Ranjith Kumar; Ward, Catherine L; Bosco, Daryl A (2014) Functions of FUS/TLS from DNA repair to stress response: implications for ALS. ASN Neuro 6:
Matus, Soledad; Bosco, Daryl A; Hetz, Claudio (2014) Autophagy meets fused in sarcoma-positive stress granules. Neurobiol Aging 35:2832-5
Auclair, Jared R; Salisbury, Joseph P; Johnson, Joshua L et al. (2014) Artifacts to avoid while taking advantage of top-down mass spectrometry based detection of protein S-thiolation. Proteomics 14:1152-7
Rotunno, Melissa S; Auclair, Jared R; Maniatis, Stephanie et al. (2014) Identification of a misfolded region in superoxide dismutase 1 that is exposed in amyotrophic lateral sclerosis. J Biol Chem 289:28527-38
Broering, Teresa J; Wang, Hongyan; Boatright, Naomi K et al. (2013) Identification of human monoclonal antibodies specific for human SOD1 recognizing distinct epitopes and forms of SOD1. PLoS One 8:e61210
Sreedharan, Jemeen; Brown Jr, Robert H (2013) Amyotrophic lateral sclerosis: Problems and prospects. Ann Neurol 74:309-16
Morfini, Gerardo A; Bosco, Daryl A; Brown, Hannah et al. (2013) Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. PLoS One 8:e65235
Rotunno, Melissa S; Bosco, Daryl A (2013) An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis. Front Cell Neurosci 7:253

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