Food(cassava) cyanogen exposure and motor neuron degeneration

Summary

Principal Investigator: DANIEL DESIRE TSHALA KATUMBAY
Abstract: Motor neuron disease is an umbrella term frequently used to designate diseases, especially neurodegenerative conditions that prominently strike the motor system in a fashion that has remained enigmatic. The existence of high incidence foci of motor neuron diseases among human populations (e.g. the Guam amyotrophic lateral sclerosis, konzo, and/or lathyrism) suggests that environmental factors e.g. exposure to certain neurotoxins cause the motor system to degenerate. The identification of such neurotoxins is highly relevant as they can be used as experimental tools to probe molecular mechanisms underlying this type of neuropathology. In our previous research, we have extensively characterized the lesion in konzo, a highly prevalent but neglected motor neuron disease occurring in sub-Saharan Africa. We have shown that konzo is a pure, permanent and irreversible disease that prominently targets the pyramidal motor tracts among populations in which the diet is almost restricted to poorly detoxified cyanogenic (linamarin)-containing cassava. In addition, affected subjects have a low intake in sulfur amino acids (SAA) needed to detoxify endogenously produced cyanide (CN). Under these conditions, oxidative metabolism of CN is favored and there is increased production of cyanate (OCN), a protein-carbamoylating agent. OCN induces myeloneuropathy in primates through mechanisms that are not understood but possibly associated with protein misfolding. SAA deficiency by itself is known to alter the activities of cystein-dependent enzymes (e.g. rodhanese) but its relationship to konzo is unkown. It is possible that SAA deficiency also alters the expression/activity of protein disulfide isomerase (PDI), an enzyme that modulates proper folding of proteins by catalyzing thiol/disulfide exchange reactions and hence, impairs the "repair" capabilities of the enzyme. We have used neuroproteomics to study mechanisms by which neurotoxic protein-reactants induce axonopathy. In this R21 project, we will use a similar approach to elucidate biomarkers of OCN/linamarin neurotoxicity and test the hypothesis that linamarin (cassava) motor neuron disease is mediated by OCN and/or SAA deficiency-sustained protein misfolding. Accordingly, we will identify (neuro)protein targets of OCN, quantify OCN adducts, characterize the neuropathology, and assess changes in selected indicators of protein misfolding in brain/spinal cord tissues of young Wistar rats kept on SAA-deficient diets and treated with linamarin, NaOCN (positive control) or equivalent amount of 5% glucose in aqueous solution (negative control) for up to 8 weeks. This line of research fits well with FIC/NIH objectives in that it addresses an issue of public health concern in the developing world while providing a neuroscience-focused framework for training and research capacity building in the Democratic Republic of Congo, a country that is currently the most affected by konzo. PUBLIC HEALTH RELEVANCE: Cassava (manioc) contains toxic compounds e.g. linamarin that are incriminated in the paralysis of legs (disease is called konzo) and other diseases of the nervous system across the lifespan. We seek funds from the Fogarty International Center/National Institutes of Health to clarify mechanisms by which it (cassava) induces neurotoxicity and to train scientists from the Democratic Republic of Congo (seriously affected by konzo) to conduct toxicological research. This project has a global heath relevance because the crop (cassava) is a staple for more than 400 million people dwelling under the tropics and it is increasingly exported worldwide for snack production and animal feed.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Diagnostic and therapeutic potential of tetanus toxin-derivatives in neurological diseases
    R Kassa
    Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University OHSU, 3181 Sam Jackson Park Road, mail code L606, Portland, OR, 97239, USA
    J Mol Neurosci 51:788-91. 2013
  2. pmc Memory deficits associated with sublethal cyanide poisoning relative to cyanate toxicity in rodents
    S Kimani
    Department of Pharmacology and Pharmacognosy and School of Nursing Sciences, University of Nairobi, Kenyatta National Hospital, P O Box 19676, Nairobi, Kenya
    Metab Brain Dis 29:105-12. 2014
  3. pmc Determinants of cognitive performance in children relying on cyanogenic cassava as staple food
    G M Bumoko
    Department of Neurology, University of Kinshasa, Kinshasa, Congo
    Metab Brain Dis 29:359-66. 2014
  4. pmc Cross-species and tissue variations in cyanide detoxification rates in rodents and non-human primates on protein-restricted diet
    S Kimani
    School of Nursing Sciences, University of Nairobi, Kenya Department of Pharmacology and Pharmacognosy, University of Nairobi, Kenya
    Food Chem Toxicol 66:203-9. 2014
  5. pmc On the biomarkers and mechanisms of konzo, a distinct upper motor neuron disease associated with food (cassava) cyanogenic exposure
    Roman M Kassa
    Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, OR, USA
    Food Chem Toxicol 49:571-8. 2011

Detail Information

Publications5

  1. pmc Diagnostic and therapeutic potential of tetanus toxin-derivatives in neurological diseases
    R Kassa
    Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University OHSU, 3181 Sam Jackson Park Road, mail code L606, Portland, OR, 97239, USA
    J Mol Neurosci 51:788-91. 2013
    ..Intramuscular delivery of Tet1-derivatives appears to be a practical approach to circumvent the blood nerve barrier and selectively deliver small molecules to the nervous system, for diagnostic and/or treatment purposes...
  2. pmc Memory deficits associated with sublethal cyanide poisoning relative to cyanate toxicity in rodents
    S Kimani
    Department of Pharmacology and Pharmacognosy and School of Nursing Sciences, University of Nairobi, Kenyatta National Hospital, P O Box 19676, Nairobi, Kenya
    Metab Brain Dis 29:105-12. 2014
    ..Differential patterns of memory deficits may reflect the differences in toxicity mechanisms of NaOCN relative to NaCN. Cognition deficits associated with cassava cyanogenesis may reflect a dual toxicity effect of cyanide and cyanate...
  3. pmc Determinants of cognitive performance in children relying on cyanogenic cassava as staple food
    G M Bumoko
    Department of Neurology, University of Kinshasa, Kinshasa, Congo
    Metab Brain Dis 29:359-66. 2014
    ..Female gender and low serum albumin are risk factors common to cognitive and proportionally associated motor deficits in children exposed to cassava cyanogens. The two types of deficits may share common mechanisms...
  4. pmc Cross-species and tissue variations in cyanide detoxification rates in rodents and non-human primates on protein-restricted diet
    S Kimani
    School of Nursing Sciences, University of Nairobi, Kenya Department of Pharmacology and Pharmacognosy, University of Nairobi, Kenya
    Food Chem Toxicol 66:203-9. 2014
    ..Chronic dietary reliance on cassava may cause metabolic derangement including poor CDC...
  5. pmc On the biomarkers and mechanisms of konzo, a distinct upper motor neuron disease associated with food (cassava) cyanogenic exposure
    Roman M Kassa
    Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, OR, USA
    Food Chem Toxicol 49:571-8. 2011
    ..g. protein disulfide isomerase), and maintenance of the cytoskeleton integrity (e.g. α-spectrin). Studies are needed to elucidate the role of the aformentioned modifications in the pathogenesis of cassava-associated motor-system disease...