Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron degenerative disease and is characterized by a progressive loss of motor neurons in the spinal cord, brain stem and cerebral cortex. It can strike adults of any age, though is most common between the ages of 50-55 years. The molecular mechanisms that cause this disease are unclear and biomarkers specific for ALS are currently unknown. Our preliminary data using mass spectrometry based proteomics identified a panel of protein biomarkers from cerebrospinal fluid (CSF) with a high level of accuracy for diagnosing ALS near the time of clinical symptom onset. We propose to examine a much larger group of ALS and control subjects to further validate and identify protein based biomarkers for ALS. The goals of this proposal are to further explore the CSF proteome of ALS and control subjects to identify peptide and/or protein biomarkers for ALS. We will utilize liquid chromatography based mass spectrometry in a large unbiased screen for peptides that distinguish ALS from control subjects. We will then validate our findings in separate subject groups and generate a mass spectrometry based method to quantify specific peptides within the CSF and/or plasma that distinguish ALS from control subjects. We will then use this panel of biomarkers to distinguish sub- populations of ALS patients based on site of disease onset, age, gender, or rate of disease progression. These studies will generate novel biomarkers for ALS that could be used in future diagnostics for ALS and tested for their ability to monitor disease progression or drug efficacy in clinical trials.

Public Health Relevance

The molecular mechanisms underlying amyotrophic lateral sclerosis (ALS) are unclear and new research directions and hypotheses are necessary to generate novel therapeutic targets. Our proposal will uncover novel peptide and protein biomarkers for ALS. These studies will lead to new insights into disease mechanisms and potential diagnostic determinants for ALS that can be further explored in future studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061867-06
Application #
8470251
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Gubitz, Amelie
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$313,898
Indirect Cost
$107,026
Name
St. Joseph's Hospital and Medical Center
Department
Type
DUNS #
131606022
City
Phoenix
State
AZ
Country
United States
Zip Code
85013
Johnson, Janel O; Pioro, Erik P; Boehringer, Ashley et al. (2014) Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci 17:664-6
Winer, Leah; Srinivasan, Dushyanth; Chun, Seung et al. (2013) SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy. JAMA Neurol 70:201-7
Ganesalingam, Jeban; An, Jiyan; Shaw, Christopher E et al. (2011) Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem 117:528-37
Ryberg, Henrik; An, Jiyan; Darko, Samuel et al. (2010) Discovery and verification of amyotrophic lateral sclerosis biomarkers by proteomics. Muscle Nerve 42:104-11
Ganesalingam, Jeban; Bowser, Robert (2010) The application of biomarkers in clinical trials for motor neuron disease. Biomark Med 4:281-97