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Moussa Youdim,오영준 한국뇌신경과학회 2013 Experimental Neurobiology Vol.22 No.3
There is an unmet need in progressive neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. The present therapeutics for these diseases at best is symptomatic and is not able to delay disease or possess disease modifying activity. Thus an approach to drug design should be made to slow or halt progressive course of a neurological disorder by interfering with a disease-specific pathogenetic process. This would entail the ability of the drug to protect neurons by blocking the common pathway for neuronal injury and cell death and the ability to promote regeneration of neurons and restoration of neuronal function. We have now developed a number of multi target drugs which possess neuroprotective, and neurorestorative activity as well as being able to active PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α), SIRT1 (NAD-dependent deacetylase protein) and NTF (mitochondrial transcription factor) that are intimately associated with mitochondrial biogenesis.
Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death
Kim, C,Yun, N,Lee, J,Youdim, M B H,Ju, C,Kim, W-K,Han, P-L,Oh, Y J Macmillan Publishers Limited 2016 CELL DEATH AND DIFFERENTIATION Vol.23 No.2
<P>Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/ threonine kinase and its dysregulation is implicated in neurodegenerative diseases. Likewise, C-terminus of Hsc70-interacting protein (CHIP) is linked to neurological disorders, serving as an E3 ubiquitin ligase for targeting damaged or toxic proteins for proteasomal degradation. Here, we demonstrate that CHIP is a novel substrate for Cdk5. Cdk5 phosphorylates CHIP at Ser20 via direct binding to a highly charged domain of CHIP. Co-immunoprecipitation and ubiquitination assays reveal that Cdk5-mediated phosphorylation disrupts the interaction between CHIP and truncated apoptosis-inducing factor (tAIF) without affecting CHIP's E3 ligase activity, resulting in the inhibition of CHIP-mediated degradation of tAIF. Lentiviral transduction assay shows that knockdown of Cdk5 or overexpression of CHIPS20A, but not CHIPWT, attenuates tAIF-mediated neuronal cell death induced by hydrogen peroxide. Thus, we conclude that Cdk5-mediated phosphorylation of CHIP negatively regulates its neuroprotective function, thereby contributing to neuronal cell death progression following neurotoxic stimuli.</P>
Oh, Chang-Ki,Han, Baek-Soo,Choi, Won-Seok,Youdim, Moussa B H,Oh, Young J Rapid Science Publishers ; Kluwer Academic Publish 2011 Apoptosis Vol.16 No.11
<P>Bax is translocated into the mitochondrial membrane and oligomerized therein to initiate mitochondrial apoptotic signaling. Our previous study indicated that reactive oxygen species (ROS)-mediated activation of mitogen-activated protein kinase (MAPK) and caspase is critically involved in 6-hydroxydopamine (6-OHDA)-mediated neurodegeneration. Here, we specifically attempted to examine whether and how these death signaling pathways may be linked to Bax translocation and oligomerization. We found that 6-OHDA treatment triggered translocation and oligomerization of Bax onto the mitochondria in MN9D dopaminergic neuronal cells. These events preceded cytochrome c release into the cytosol. Cross-linking assay revealed that co-treatment with a ROS scavenger or a pan-caspase inhibitor inhibited 6-OHDA-induced Bax oligomerization. Among several candidates of ROS-activated MAPKs and caspases, we found that co-treatment with PD169316 or VDVAD specifically inhibited 6-OHDA-induced Bax oligomerization, suggesting critical involvement of p38 MAPK and caspase-2. Consequently, overexpression of a dominant negative form of p38 MAPK or a shRNA-mediated knockdown of caspase-2 indeed inhibited 6-OHDA-induced Bax oligomerization. However, activation of p38 MAPK and caspase-2 was independently linked to oligomerization of Bax. This specificity was largely confirmed with a Bax 6A7 antibody known to detect activated forms of Bax on the mitochondria. Taken together, our data suggest that there is an independent amplification loop of Bax translocation and oligomerization via caspase-2 and p38 MAPK during ROS-mediated dopaminergic neurodegeneration.</P>
Shin, E. J.,Nam, Y.,Lee, J. W.,Nguyen, P. K.,Yoo, J. E.,Tran, T. V.,Jeong, J. H.,Jang, C. G.,Oh, Y. J.,Youdim, M. B. HUMANA PRESS INC 2016 Molecular Neurobiology Vol.53 No.9
<P>Selegiline is a monoamine oxidase-B (MAO-B) inhibitor with anti-Parkinsonian effects, but it is metabolized to amphetamines. Since another MAO-B inhibitor N-Methyl, N-propynyl-2-phenylethylamine (MPPE) is not metabolized to amphetamines, we examined whether MPPE induces behavioral side effects and whether MPPE affects dopaminergic toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Multiple doses of MPPE (2.5 and 5 mg/kg/day) did not show any significant locomotor activity and conditioned place preference, whereas selegiline (2.5 and 5 mg/kg/day) significantly increased these behavioral side effects. Treatment with MPPE resulted in significant attenuations against decreases in mitochondrial complex I activity, mitochondrial Mn-SOD activity, and expression induced by MPTP in the striatum of mice. Consistently, MPPE significantly attenuated MPTP-induced oxidative stress and MPPE-mediated antioxidant activity appeared to be more pronounced in mitochondrial-fraction than in cytosolic-fraction. Because MPTP promoted mitochondrial p53 translocation and p53/Bcl-xL interaction, it was also examined whether mitochondrial p53 inhibitor pifithrin-mu attenuates MPTP neurotoxicity. MPPE, selegiline, or pifithrin-mu significantly attenuated mitochondrial p53/Bcl-xL interaction, impaired mitochondrial transmembrane potential, cytosolic cytochrome c release, and cleaved caspase-3 in wild-type mice. Subsequently, these compounds significantly ameliorated MPTP-induced motor impairments. Neuroprotective effects of MPPE appeared to be more prominent than those of selegiline. MPPE or selegiline did not show any additional protective effects against the attenuation by p53 gene knockout, suggesting that p53 gene is a critical target for these compounds. Our results suggest that MPPE possesses anti-Parkinsonian potentials with guaranteed behavioral safety and that the underlying mechanism of MPPE requires inhibition of mitochondrial oxidative stress, mitochondrial translocation of p53, and pro-apoptotic process.</P>