A study of potential sporadic amyotrophic lateral sclerosis biomarkers in cerebrospinal fluid

Sporadic Amyotrophic Lateral Sclerosis (sALS) is a debilitating and fatal neurodegenerative disease of unknown etiology. It currently has no biochemical marker to confirm a clinical diagnosis, and this has negative consequences for patients when it comes to initiating early medical intervention and participating in therapeutic trials. Valid biomarkers can be useful for diagnostic and prognostic indications as well as providing insight into disease pathogenesis and identifying targets for therapeutic interventions. Cerebrospinal fluid (CSF) may be a particularly valuable source of biomarkers because it is in close anatomical proximity to the brain and spinal cord, thus making it a better reflection of biochemical alterations resulting from neurodegenerative disease. This study examined the proteome profile of CSF from sALS patients and controls to identify candidate biomarkers that might aid in the diagnosis of sALS and possibly provide insight into disease pathogenesis. An antibody microarray technique was used to measure the expression levels of various cell signalling proteins in the CSF of sALS patients and healthy controls. The results identified a number of protein changes in sALS CSF, including a considerable decrease in the level of ephrin type-A receptor 1 tyrosine kinase (EphA1) relative to control CSF. Follow-up validation studies by Western blotting with CSF samples from a separate cohort of 19 sALS patients, 21 healthy controls and 10 neurological disease controls confirmed a statistically significant decrease in EphA1 levels. As a diagnostic test, EphA1 levels in CSF had a statistically significant ability to discriminate between sALS patients and controls. Receptor levels also had a positive correlation with age at onset of sALS symptoms, indicating that this potential biomarker may be capable of identifying people who are prone to an earlier onset of disease. The Eph family of tyrosine kinase receptors engage in complex bidirectional signalling that functions as a major form of contact-dependent communication between cells, and mediates a variety of cellular responses. As research begins to further elucidate these multifaceted signalling mechanisms, imbalances in Eph receptor functioning are increasingly implicated in a variety of pathologies in the central nervous system that are related to some of the major features of ALS.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat