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  1. Ching-Hua Lu, Axel Petzold, Bernadett Kalmar, James Dick, Andrea Malaspina and Linda Greensmith.
    Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A) mice that model ALS.. PloS one 7(7):e40998, 2012.
    Abstract BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3-5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials. METHODOLOGY/PRINCIPAL FINDINGS: In this study, using the well-established SOD1(G93A) mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1(G93A) mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials. CONCLUSIONS/SIGNIFICANCE: These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1(G93A) mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS.
    URL, DOI BibTeX

    @article{Lu2012,
    	abstract = "BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3-5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials. METHODOLOGY/PRINCIPAL FINDINGS: In this study, using the well-established SOD1(G93A) mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1(G93A) mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials. CONCLUSIONS/SIGNIFICANCE: These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1(G93A) mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS.",
    	author = "Lu, Ching-Hua and Petzold, Axel and Kalmar, Bernadett and Dick, James and Malaspina, Andrea and Greensmith, Linda",
    	doi = "10.1371/journal.pone.0040998",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lu et al. - 2012 - Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response.pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Animals,Biological Markers,Biological Markers: metabolism,Disease Models, Animal,Disease Progression,Enzyme-Linked Immunosorbent Assay,Enzyme-Linked Immunosorbent Assay: methods,Female,Hydroxylamines,Hydroxylamines: pharmacology,Mice,Mice, Inbred C57BL,Mice, Transgenic,Muscles,Muscles: metabolism,Neurofilament Proteins,Neurofilament Proteins: blood,Neurofilament Proteins: chemistry,Phosphorylation,Spinal Cord,Spinal Cord: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics,Treatment Outcome",
    	month = "",
    	number = 7,
    	pages = "e40998",
    	pmid = 22815892,
    	title = "{Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A) mice that model ALS.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3397981\&tool=pmcentrez\&rendertype=abstract",
    	volume = 7,
    	year = 2012
    }
    
  2. Kevin Boylan, Cui Yang, Julia Crook, Karen Overstreet, Michael Heckman, Yong Wang, David Borchelt and Gerry Shaw.
    Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF-H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF-H as a potential ALS biomarker.. Journal of neurochemistry 111(5):1182–91, 2009.
    Abstract Levels of neurofilament subunits, potential biomarkers of motor axon breakdown, are increased in amyotrophic lateral sclerosis (ALS) patient's CSF but data on blood are not available. We measured blood levels of the phosphorylated axonal form of neurofilament H (pNF-H) by ELISA in transgenic rodent models of superoxide dismutase 1 (SOD1) ALS, and in 20 ALS patients and 20 similar aged controls monthly for 4 months. All symptomatic rodent ALS models showed robust levels of blood pNF-H, while control rodents or mice transgenic for unmutated SOD1 showed no detectable blood pNF-H. Average pNF-H levels in the G93A SOD1 mouse progressively increased from day 74 through death (day approximately 130). Median blood pNF-H level in ALS patients was 2.8-fold higher than controls (p < 0.001). Median ALSFRS-R declined a median of 0.8 pt/month (p < 0.001); higher baseline pNF-H level appeared to be associated with faster ALSFRS-R decline over 4 months (p = 0.087). The median rate of decline in ALSFRS-R was 1.9 pt/month in patients with baseline pNF-H levels above the median pNF-H value of 0.53 ng/mL; ALSFRS-R declined at a median of 0.6 pt/month in patients below this level. The pNF-H levels were relatively stable month to month in individual patients, raising questions regarding the molecular pathogenesis of ALS. Baseline control human pNF-H levels were higher in men than women and increased minimally over time. These data suggest that blood pNF-H can be used to monitor axonal degeneration in ALS model rodents and support further study of this protein as a potential biomarker of disease prognosis in ALS patients.
    URL, DOI BibTeX

    @article{Boylan2009,
    	abstract = "Levels of neurofilament subunits, potential biomarkers of motor axon breakdown, are increased in amyotrophic lateral sclerosis (ALS) patient's CSF but data on blood are not available. We measured blood levels of the phosphorylated axonal form of neurofilament H (pNF-H) by ELISA in transgenic rodent models of superoxide dismutase 1 (SOD1) ALS, and in 20 ALS patients and 20 similar aged controls monthly for 4 months. All symptomatic rodent ALS models showed robust levels of blood pNF-H, while control rodents or mice transgenic for unmutated SOD1 showed no detectable blood pNF-H. Average pNF-H levels in the G93A SOD1 mouse progressively increased from day 74 through death (day approximately 130). Median blood pNF-H level in ALS patients was 2.8-fold higher than controls (p < 0.001). Median ALSFRS-R declined a median of 0.8 pt/month (p < 0.001); higher baseline pNF-H level appeared to be associated with faster ALSFRS-R decline over 4 months (p = 0.087). The median rate of decline in ALSFRS-R was 1.9 pt/month in patients with baseline pNF-H levels above the median pNF-H value of 0.53 ng/mL; ALSFRS-R declined at a median of 0.6 pt/month in patients below this level. The pNF-H levels were relatively stable month to month in individual patients, raising questions regarding the molecular pathogenesis of ALS. Baseline control human pNF-H levels were higher in men than women and increased minimally over time. These data suggest that blood pNF-H can be used to monitor axonal degeneration in ALS model rodents and support further study of this protein as a potential biomarker of disease prognosis in ALS patients.",
    	author = "Boylan, Kevin and Yang, Cui and Crook, Julia and Overstreet, Karen and Heckman, Michael and Wang, Yong and Borchelt, David and Shaw, Gerry",
    	doi = "10.1111/j.1471-4159.2009.06386.x",
    	issn = "1471-4159",
    	journal = "Journal of neurochemistry",
    	keywords = "Adult,Age Factors,Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: pathology,Animals,Axons,Axons: metabolism,Biological Markers,Biological Markers: blood,Disease Models, Animal,Disease Progression,Enzyme-Linked Immunosorbent Assay,Enzyme-Linked Immunosorbent Assay: methods,Female,Gene Expression Regulation,Gene Expression Regulation: genetics,Humans,Male,Mice,Mice, Transgenic,Middle Aged,Mutation,Mutation: genetics,Neurofilament Proteins,Neurofilament Proteins: blood,Neurons,Neurons: pathology,Nuclear Proteins,Nuclear Proteins: metabolism,Phosphorylation,Superoxide Dismutase,Superoxide Dismutase: genetics,Suppressor of Cytokine Signaling Proteins,Suppressor of Cytokine Signaling Proteins: metabol",
    	month = "",
    	number = 5,
    	pages = "1182--91",
    	pmid = 19765193,
    	title = "{Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF-H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF-H as a potential ALS biomarker.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/19765193",
    	volume = 111,
    	year = 2009
    }
    

 

http://www.sciencedaily.com/releases/2014/04/140403131744.htm

Referred paper: Modeling ALS with iPSCs Reveals that Mutant SOD1 Misregulates Neurofilament Balance in Motor Neurons

Summary

Amyotrophic lateral sclerosis (ALS) presents motoneuron (MN)-selective protein inclusions and axonal degeneration but the underlying mechanisms of such are unknown. Using induced pluripotent cells (iPSCs) from patients with mutation in the Cu/Zn superoxide dismutase (SOD1) gene, we show that spinal MNs, but rarely non-MNs, exhibited neurofilament (NF) aggregation followed by neurite degeneration when glia were not present. These changes were associated with decreased stability of NF-L mRNA and binding of its 3′ UTR by mutant SOD1 and thus altered protein proportion of NF subunits. Such MN-selective changes were mimicked by expression of a single copy of the mutant SOD1 in human embryonic stem cells and were prevented by genetic correction of the SOD1 mutation in patient’s iPSCs. Importantly, conditional expression of NF-L in the SOD1 iPSC-derived MNs corrected the NF subunit proportion, mitigating NF aggregation and neurite degeneration. Thus, NF misregulation underlies mutant SOD1-mediated NF aggregation and axonal degeneration in ALS MNs.