Abstract
Objective biomarkers for amyotrophic lateral sclerosis would facilitate the discovery of new treatments. The common neurotrophin receptor p75 is up regulated and the extracellular domain cleaved from injured neurons and peripheral glia in amyotrophic lateral sclerosis. We have tested the hypothesis that urinary levels of extracellular neurotrophin receptor p75 serve as a biomarker for both human motor amyotrophic lateral sclerosis and the SOD1G93A mouse model of the disease. The extracellular domain of neurotrophin receptor p75 was identified in the urine of amyotrophic lateral sclerosis patients by an immuno-precipitation/western blot procedure and confirmed by mass spectrometry. An ELISA was established to measure urinary extracellular neurotrophin receptor p75. The mean value for urinary extracellular neurotrophin receptor p75 from 28 amyotrophic lateral sclerosis patients measured by ELISA was 7.9±0.5 ng/mg creatinine and this was significantly higher (p<0.001) than 12 controls (2.6±0.2 ng/mg creatinine) and 19 patients with other neurological disease (Parkinson's disease and Multiple Sclerosis; 4.1±0.2 ng/mg creatinine). Pilot data of disease progression rates in 14 MND patients indicates that p75NTRECD levels were significantly higher (p = 0.0041) in 7 rapidly progressing patients as compared to 7 with slowly progressing disease. Extracellular neurotrophin receptor p75 was also readily detected in SOD1G93A mice by immuno-precipitation/western blot before the onset of clinical symptoms. These findings indicate a significant relation between urinary extracellular neurotrophin receptor p75 levels and disease progression and suggests that it may be a useful marker of disease activity and progression in amyotrophic lateral sclerosis.
Highlights
Amyotrophic lateral sclerosis (ALS) or Motor neuron disease (MND) is a disease characterised by progressive, debilitating paralysis from loss of motor neurons in the cerebral cortex, brain stem and spinal cord and is almost always fatal
To our knowledge this is the first time that urinary p75NTRECD has been proposed as a candidate marker of ALS/MND. p75NTR mediates dual opposing functions of cell survival and death that is controlled by the presence or absence of neurotrophins and includes apoptosis in the adult nervous system upon injury and degeneration [31]
In our pilot study of 28 ALS patients and 12 controls we have definitively identified p75NTRECD in human urine of ALS patients and shown the mean levels are near to 3 fold higher than healthy controls (7.860.5 versus 2.660.3 ng/mg creatinine)
Summary
Amyotrophic lateral sclerosis (ALS) or Motor neuron disease (MND) is a disease characterised by progressive, debilitating paralysis from loss of motor neurons in the cerebral cortex, brain stem and spinal cord and is almost always fatal. At present there is an urgent need for marker(s) able to measure disease progression for objective monitoring of therapies for human clinical trials and pre-clinical SOD1G93A mice trials [2]. The only validated markers for disease progression are a subjective measure of disability and breathing, called the revised ALS functional rating scale (ALSFRS-r) with a scale from 0 to 48, and time to death [3]. The ALSFRS-r, the most powerful marker at present is neither objective nor sensitive in the short term, given that individuals are so variable in the course of their disease. Biomarkers that reflect disease progression objectively in both human and mice will improve the analysis of clinical trials and allow for more rapid screening of potential new treatments with fewer patients than required for standard placebo-controlled trials
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