Analysis of Post-Translational Modifications of a Critical Protein Implicated in Amyotrophic Lateral Sclerosis
| Status: | Completed |
|---|---|
| Conditions: | Neurology, Neurology, Neurology, ALS |
| Therapuetic Areas: | Neurology, Other |
| Healthy: | No |
| Age Range: | 18 - 99 |
| Updated: | 10/19/2018 |
| Start Date: | August 2014 |
| End Date: | October 16, 2018 |
The purpose of this research study is to discover and quantitate the differences in
post-translational modifications found in the Cu, Zn superoxide dismutase (SOD1) of patients
with amyotrophic lateral sclerosis (ALS) as compared to healthy individuals. SOD1 is a known
genetic cause of ALS. With certain mutations, SOD1 gains a toxic function which leads to
motor neuron death.
post-translational modifications found in the Cu, Zn superoxide dismutase (SOD1) of patients
with amyotrophic lateral sclerosis (ALS) as compared to healthy individuals. SOD1 is a known
genetic cause of ALS. With certain mutations, SOD1 gains a toxic function which leads to
motor neuron death.
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease in which
mutations in human Cu, Zn Superoxide Dismutase (SOD1) have been identified as a cause of
familial ALS (FALS) cases.1-2 It has been shown that mutant SOD1 develops a novel toxic
function through experiments demonstrating that many disease mutants maintain enzymatic
activity, SOD1-null mice do not exhibit ALS symptoms, and co-expressed wild type protein does
not rescue the disease-state.7-11 The majority of cases, however, are not caused directly by
mutations of SOD1, instead being caused by a poorly understood interplay of several genes as
well as environmental factors, which is often referred to as sporadic ALS (SALS).3 It has
been found that FALS and SALS share similar pathology. 4-6 The hSOD1 protein aggregates
characteristic of FALS have also been found in SALS patients, furthering the evidence that
hSOD1 has an important role in the etiology of ALS in sporadic ALS patients.16-19 The exact
mechanism of SOD1-associated toxicity has not yet been elucidated though many disease mutants
have been shown to destabilize the SOD1 dimer. In this study we aim to compare the levels of
SOD1 post-tra slational modifications in ALS patients to levels in healthy donors and to
determine if there are distinct patterns of protein glutathionylation or phosphorylation. Our
overall goal is to elucidate a direct mechanism of toxicity in SALS as well as identify
potentially critical triggers
mutations in human Cu, Zn Superoxide Dismutase (SOD1) have been identified as a cause of
familial ALS (FALS) cases.1-2 It has been shown that mutant SOD1 develops a novel toxic
function through experiments demonstrating that many disease mutants maintain enzymatic
activity, SOD1-null mice do not exhibit ALS symptoms, and co-expressed wild type protein does
not rescue the disease-state.7-11 The majority of cases, however, are not caused directly by
mutations of SOD1, instead being caused by a poorly understood interplay of several genes as
well as environmental factors, which is often referred to as sporadic ALS (SALS).3 It has
been found that FALS and SALS share similar pathology. 4-6 The hSOD1 protein aggregates
characteristic of FALS have also been found in SALS patients, furthering the evidence that
hSOD1 has an important role in the etiology of ALS in sporadic ALS patients.16-19 The exact
mechanism of SOD1-associated toxicity has not yet been elucidated though many disease mutants
have been shown to destabilize the SOD1 dimer. In this study we aim to compare the levels of
SOD1 post-tra slational modifications in ALS patients to levels in healthy donors and to
determine if there are distinct patterns of protein glutathionylation or phosphorylation. Our
overall goal is to elucidate a direct mechanism of toxicity in SALS as well as identify
potentially critical triggers
Inclusion Criteria:
- SALS patients
- SOD1 associated FALS patients
- Healthy control
Exclusion Criteria: none
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