1) Posttranslational oxidative modification of Cu-Zn superoxide dismutase (SOD1) as a mechanism of motor neuron death in ALS; SOD1 is a 16KD protein with a known function of converting superoxide to water and hydrogen peroxide. Mutations in the SOD1 gene are linked to ALS, and cause motoneuron degeneration by a gain of toxic properties. Recent studies from others and my laboratory support that the gain of toxic properties of mutant SOD1 may result from oxidation of its cysteine residues. Our working hypothesis is that the onset of ALS is triggered by SOD1 oxidization. Specifically, we hypothesize that: 1) Posttranslational oxidation of SOD1 triggers the formation of SOD1 aggregates leading to motor neuron death; 2) Mutant SOD1 proteins are not toxic until they are oxidized, and oxidized wild type SOD1 protein becomes toxic to motor neurons; 3) mutant SOD1 proteins are more prone to oxidation in oxidative stress than wild-type SOD1; 4) Anti-oxidation prevents oxidized SOD1-induced motor neuron death.
2) Rescue of neuronal death in stroke and ALS by targeting the BNIP3 pathway; A growing number of recent studies supports that neuronal death in neurodegenerative diseases is largely mediated by caspase-independent apoptosis pathways. We have reported that at least one form of the caspase-independent apoptosis is activated by the proapoptotic gene BNIP3. Recently, we have obtained data to suggest strongly that BNIP3 plays a role in neuronal death in ALS and stroke. Our general hypothesis is that BNIP3 is a regulator of neuronal death in ALS and stroke, and inhibition of BNIP3 protects neurons from death in animal models of ALS and stroke. We are currently defining the BNIP3 pathway and developing strategies to protect neurons from death in animal models of ALS and stroke by targeting the BNIP3 pathway.
3) Testing the demyelination hypothesis of schizophrenia. Schizophrenia is a severe mental disorder that affects up to 1% of the Canadian and worldwide population. Current observations support an oligodendrocyte (OL) dysfunction hypothesis. This hypothesis, however, has never been experimentally tested due to the lack of suitable animal models. We have revisited a cuprizone (CPZ)-induced demyelination model, and found that this model appears to be suitable for testing the OL dysfunction hypothesis of schizophrenia. Our hypothesis is that altered connectivity, resulting from OL dysfunction, demyelination and factors affecting myelination, plays a role in the pathogenesis of schizophrenia. Specifically, we hypothesize that OL dysfunction and demyelination causes schizophrenia-like behaviours, and promoting remyelination attenuates CPZ-induced schizophrenia-like behaviours.
Recent publications:
1) Yu Y, He J, Zhang Y, Luo H, Zhu S, Yang Y, Zhao T, Wu J, Huang Y, Kong J, Tan Q, Li XM (2009): Increased hippocampal neurogenesis in the progressive stage of Alzheimer’s disease phenotype in an APP/PS1 double transgenic mouse model. Hippocampus (in press).
2) Bi X, Yan B, Fang S, He J, Li XM and Kong J. (2009) Quetiapine regulates neurogenesis in ischemic mice by inhibiting NFB p65/p50 expression. Neurological Research (Accepted Nov, 2008, In press).
3) Zhang Y, Xu H, Jiang W, Xiao L, Yan B, He J, Wang Ya, Bi X, Li X, Kong J and Li XM. (2008) Quetiapine alleviates the cuprizone-induced white matter pathology in the brain of C57BL/6 mouse. Schizophrenia Research 106:182-191.
4) Xu H, Wang H, Zhuang L, Yan B, Yu Y, Wei Z, Zhang Y, Dyck LE, Richardson SJ, He J, Li X, Kong J and Li XM. (2008) Demonstration of an anti-oxidative stress mechanism of quetiapine: Implications for the treatment of Alzheimer’s disease. FEBS Journal, 275(14):3718-3728.
5) Chen Y, McMillan-Ward E, Kong J, Israels SJ and Gibson SB. (2008) Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death and Differentiation, 15:171-182.
6) Chen Y, McMillian-Ward E, Kong J, Isreals SJ and Gibson S. (2007) Mitochondrial electron transport chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. Journal of Cell Science 120: 4155-4166.
7) Yan B, Bi X, He J, Zhang Y, Thakur S, Xu H, Gendron A, Kong J, Li XM. (2007) Quetiapine attenuates spatial memory impairment and hippocampal neurodegeneration induced by bilateral common carotid artery occlusion in mice. Life Science 81(5):353-361.
8) Xu X, Chua CC, Kong J , Kostrzewa RM, Kumaraguru U, Hamdy RC and Chua BHL. (2007) Necrostatin-1 protects against glutamate-induced GSH depletion and caspase-independent cell death in HT-22 cells. Journal of Neurochemistry, 103:2004-2014.
9) Yan B, He J, Xu H, Zhang Y, Bi X, Thakur S, Gendron A, Kong J and Li XM. (2007) Quetiapine attenuates the depressive and anxiolytic-like behavioural changes induced by global cerebral ischemia in mice. Behavioural Brain Research 182:36-41.
10) Zhang Z, Yang X, Zhang S, Ma X and Kong J. (2007) BNIP3 upregulation and EndoG translocaiton in delayed neuronal death in stroke and in hypoxia. Stroke 38 (5), 1606-1613
11) Zhang S, Zhang Z, Sandhu G, Ma X, Yang X, Geiger JD and Kong J. (2007) Evidence of oxidative stress-induced BNIP3 expression in amyloid beta neurotoxicity. Brain Research 1138:221-230.