Role of the prolyl isomerase Pin1 in the pathogenesis of Parkinson\u27s disease and neuroprotection by novel targeted compounds in pre-clinical animal models of the disease

Parkinson\u27s disease (PD) is a chronic and progressive neurodegenerative disorder named by the French neurologist Jean-Martin Charot, after the British physician James Parkinson who first described the disease as Shaking Palsy . Pathologically, PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), a marked reduction of dopamine in the striatum, the presence of ubiquitin and α-synuclein positive cytoplasmic inclusions known as Lewy bodies, and depigmentation of the locus cereleus. The prevailing theory regarding processes that are likely to account for progressive degeneration of the dopaminergic neurons in the nigrostriatal axis involves on mitochondrial dysfunction, oxidative stress, excitotoxicity and neuroinflammation. Of those, neuroinflammation and oxidative stress have gained the most focus recently. Research over the last decade has provided extensive evidence that the sustained microglial and astroglial neuroinflammatory responses cause progressive and delayed dopaminergic neurodegeneration. However, the mechanisms by which glial cells activation and subsequent inflammation lead to dopaminergic neurodegeneration remain poorly understood. Development of effective therapeutic approaches to halt the disease progression of PD is of paramount importance. My objective in this Ph.D. thesis work was to characterize important signaling molecules activated in neuroinflammation mediated neurodegenerative pathways as well as characterze of novel compounds in a pre-clinical mouse model of PD. Protein interacting with never in mitosis - A (Pin1) is a peptidyl-prolyl isomerase, that specifically recognizes phosphorylated serine or threonine residues immediately preceding proline (pSer/Thr-Pro) in a subset of proteins in which it isomerizes the cis/trans conformation of the peptide bond. High expression levels of Pin1 in terminally differentiated and post mitotic neurons suggest that it plays an important role in neurons, except in cell cycle regulation and proliferation. Recently, Pin1 overexpression was shown to facilitate formation of &alpha-synuclein inclusions in a cellular model of &alpha-synuclein aggregation. Pin1 was also localized in Lewy bodies in PD patients. But the level, activity, and role of Pin1 in the pathogenesis of PD are incompletely known. We hypothesized that Pin1 is differentially activated in neuronal and glial cells of the nigral dopaminergic system, and that it regulates NF-κB-mediated sustained neuroinflammatory processes in cell culture and in an animal model of Parkinson\u27s disease. Herein, we demonstrate for the first time that there is a dopaminergic neuron specific upregulation of Pin1 in human postmortem PD brain sections as well as in cell culture and animal models. We observed a rapid increase in Pin1 expression in both the 1-methyl-4phenyl pyridinium (MPP+)-treated cell culture and in 1-methyl-4-phenyl-1-2-3-6-tetrahydroptridine MPTP treated mice. Also, Pin1 acts as an important pro-apoptotic factor in the selective degeneration of dopaminergic neurons. Importantly, pharmacological inhibition of Pin1 attenuates MPTP-induced Pin1 expression in vitro and in vivo and protects against MPTP-induced neurodegeneration in the nigrostriatal axis. We also demonstrate for the first time that, microglia and astrocytes express Pin1 and that there is a strong association between Pin1 and NF-κB p65 in BV2 microglial cells. Recent studies demonstrated that the promoter regions of proinflammatory molecules contain the DNA binding site for NF-κB. We have shown that Pin1 and NF-κB p65 inhibition by Juglone leads to attenuation of glial cells activation and subsequent reduction of proinflammatory reactions in cell culture and in an animal model of PD. While characterizing the role of Pin1 in the pathogenesis of PD, we also tested the efficacy of novel compounds for protection of dopaminergic neurons in a mouse model of PD. We demonstrate that the novel compound diapocynin, a metabolite of apocynin, blocks MPTP-induced activation of microglial and astroglial cells, thus inhibiting the inflammatory and oxidative stress processes in MPTP-treated mice. Diapocynin also protects the nigrostriatum against MPTP toxicity. The final chapter of this work characterizes the anti-inflammatory and neuroprotective properties of mito-apocynin, a mitochondria targeted compound in the MPTP mouse model of PD. Mitoapocynin prevents the behavioral imapariments and dopamine loss caused by MPTP-induced toxicity. We have shown that mito-apocynin protects the nigrostriatum by attenuating glial cell mediated neuroinflammation and oxidative stress. Collectively, the research described herein characterizes the novel and important roles of Pin1 in the neuroinflammation and pathophysiology of Parkinson\u27s disease, as well as establishes the efficacy of novel compounds in protection of the nigrostriatum in a pre-clinical mouse model of Parkinson\u27s disease

Characteristics of Bay of Bengal monsoon depressions in the 21st Century

We show that 21st century increase in radiative forcing does not significantly impact the frequency of South Asian summer monsoon depressions (MDs) or their trajectories in the Coupled Model Intercomparison Project Phase 5 general circulation models (GCMs). A significant relationship exists between the climatological occurrences of MDs and the strength of the background upper (lower) tropospheric meridional (zonal) winds and tropospheric moisture in the core genesis region of MDs. Likewise, there is a strong relationship between the strength of the meridional tropospheric temperature gradient in the GCMs and the trajectories of MDs over land. While monsoon dynamics progressively weakens in the future, atmospheric moisture exhibits a strong increase, limiting the impact of changes in dynamics on the frequency of MDs. Moreover, the weakening of meridional tropospheric temperature gradient in the future is substantially weaker than its inherent underestimation in the GCMs. Our results also indicate that future increases in the extreme wet events are dominated by nondepression day occurrences, which may render the monsoon extremes less predictable in the future

Sodium Phenylbutyrate Controls Neuroinflammatory and Antioxidant Activities and Protects Dopaminergic Neurons in Mouse Models of Parkinson’s Disease

Neuroinflammation and oxidative stress underlie the pathogenesis of various neurodegenerative disorders. Here we demonstrate that sodium phenylbutyrate (NaPB), an FDA-approved therapy for reducing plasma ammonia and glutamine in urea cycle disorders, can suppress both proinflammatory molecules and reactive oxygen species (ROS) in activated glial cells. Interestingly, NaPB also decreased the level of cholesterol but involved only intermediates, not the end product of cholesterol biosynthesis pathway for these functions. While inhibitors of both geranylgeranyl transferase (GGTI) and farnesyl transferase (FTI) inhibited the activation of NF-κB, inhibitor of GGTI, but not FTI, suppressed the production of ROS. Accordingly, a dominant-negative mutant of p21rac, but not p21ras, attenuated the production of ROS from activated microglia. Inhibition of both p21ras and p21rac activation by NaPB in microglial cells suggests that NaPB exerts anti-inflammatory and antioxidative effects via inhibition of these small G proteins. Consistently, we found activation of both p21ras and p21rac in vivo in the substantia nigra of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. Oral administration of NaPB reduced nigral activation of p21ras and p21rac, protected nigral reduced glutathione, attenuated nigral activation of NF-κB, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Consistently, FTI and GGTI also protected nigrostriata in MPTP-intoxicated mice. Furthermore, NaPB also halted the disease progression in a chronic MPTP mouse model. These results identify novel mode of action of NaPB and suggest that NaPB may be of therapeutic benefit for neurodegenerative disorders

Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice

Aims: Parkinson\u27s disease (PD) is a neurodegenerative disorder characterized by progressive motor deficits and degeneration of dopaminergic neurons. Caused by a number of genetic and environmental factors, mitochondrial dysfunction and oxidative stress play a role in neurodegeneration in PD. By selectively knocking out mitochondrial transcription factor A (TFAM) in dopaminergic neurons, the transgenic MitoPark mice recapitulate many signature features of the disease, including progressive motor deficits, neuronal loss, and protein inclusions. In the present study, we evaluated the neuroprotective efficacy of a novel mitochondrially targeted antioxidant, Mito-apocynin, in MitoPark mice and cell culture models of neuroinflammation and mitochondrial dysfunction. Results: Oral administration of Mito-apocynin (10 mg/kg, thrice a week) showed excellent central nervous system bioavailability and significantly improved locomotor activity and coordination in MitoPark mice. Importantly, Mito-apocynin also partially attenuated severe nigrostriatal degeneration in MitoPark mice. Mechanistic studies revealed that Mito-apo improves mitochondrial function and inhibits NOX2 activation, oxidative damage, and neuroinflammation. Innovation: The properties of Mito-apocynin identified in the MitoPark transgenic mouse model strongly support potential clinical applications for Mito-apocynin as a viable neuroprotective and anti-neuroinflammatory drug for treating PD when compared to conventional therapeutic approaches. Conclusion: Collectively, our data demonstrate, for the first time, that a novel orally active apocynin derivative improves behavioral, inflammatory, and neurodegenerative processes in a severe progressive dopaminergic neurodegenerative model of PD. Antioxid. Redox Signal. 27, 1048–1066

Role of the prolyl isomerase Pin1 in the pathogenesis of Parkinson's disease and neuroprotection by novel targeted compounds in pre-clinical animal models of the disease

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder named by the French neurologist Jean-Martin Charot, after the British physician James Parkinson who first described the disease as "Shaking Palsy". Pathologically, PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), a marked reduction of dopamine in the striatum, the presence of ubiquitin and α-synuclein positive cytoplasmic inclusions known as Lewy bodies, and depigmentation of the locus cereleus. The prevailing theory regarding processes that are likely to account for progressive degeneration of the dopaminergic neurons in the nigrostriatal axis involves on mitochondrial dysfunction, oxidative stress, excitotoxicity and neuroinflammation. Of those, neuroinflammation and oxidative stress have gained the most focus recently. Research over the last decade has provided extensive evidence that the sustained microglial and astroglial neuroinflammatory responses cause progressive and delayed dopaminergic neurodegeneration. However, the mechanisms by which glial cells activation and subsequent inflammation lead to dopaminergic neurodegeneration remain poorly understood. Development of effective therapeutic approaches to halt the disease progression of PD is of paramount importance. My objective in this Ph.D. thesis work was to characterize important signaling molecules activated in neuroinflammation mediated neurodegenerative pathways as well as characterze of novel compounds in a pre-clinical mouse model of PD. Protein interacting with never in mitosis - A (Pin1) is a peptidyl-prolyl isomerase, that specifically recognizes phosphorylated serine or threonine residues immediately preceding proline (pSer/Thr-Pro) in a subset of proteins in which it isomerizes the cis/trans conformation of the peptide bond. High expression levels of Pin1 in terminally differentiated and post mitotic neurons suggest that it plays an important role in neurons, except in cell cycle regulation and proliferation. Recently, Pin1 overexpression was shown to facilitate formation of &alpha-synuclein inclusions in a cellular model of &alpha-synuclein aggregation. Pin1 was also localized in Lewy bodies in PD patients. But the level, activity, and role of Pin1 in the pathogenesis of PD are incompletely known. We hypothesized that Pin1 is differentially activated in neuronal and glial cells of the nigral dopaminergic system, and that it regulates NF-κB-mediated sustained neuroinflammatory processes in cell culture and in an animal model of Parkinson's disease. Herein, we demonstrate for the first time that there is a dopaminergic neuron specific upregulation of Pin1 in human postmortem PD brain sections as well as in cell culture and animal models. We observed a rapid increase in Pin1 expression in both the 1-methyl-4phenyl pyridinium (MPP+)-treated cell culture and in 1-methyl-4-phenyl-1-2-3-6-tetrahydroptridine MPTP treated mice. Also, Pin1 acts as an important pro-apoptotic factor in the selective degeneration of dopaminergic neurons. Importantly, pharmacological inhibition of Pin1 attenuates MPTP-induced Pin1 expression in vitro and in vivo and protects against MPTP-induced neurodegeneration in the nigrostriatal axis. We also demonstrate for the first time that, microglia and astrocytes express Pin1 and that there is a strong association between Pin1 and NF-κB p65 in BV2 microglial cells. Recent studies demonstrated that the promoter regions of proinflammatory molecules contain the DNA binding site for NF-κB. We have shown that Pin1 and NF-κB p65 inhibition by Juglone leads to attenuation of glial cells activation and subsequent reduction of proinflammatory reactions in cell culture and in an animal model of PD. While characterizing the role of Pin1 in the pathogenesis of PD, we also tested the efficacy of novel compounds for protection of dopaminergic neurons in a mouse model of PD. We demonstrate that the novel compound diapocynin, a metabolite of apocynin, blocks MPTP-induced activation of microglial and astroglial cells, thus inhibiting the inflammatory and oxidative stress processes in MPTP-treated mice. Diapocynin also protects the nigrostriatum against MPTP toxicity. The final chapter of this work characterizes the anti-inflammatory and neuroprotective properties of mito-apocynin, a mitochondria targeted compound in the MPTP mouse model of PD. Mitoapocynin prevents the behavioral imapariments and dopamine loss caused by MPTP-induced toxicity. We have shown that mito-apocynin protects the nigrostriatum by attenuating glial cell mediated neuroinflammation and oxidative stress. Collectively, the research described herein characterizes the novel and important roles of Pin1 in the neuroinflammation and pathophysiology of Parkinson's disease, as well as establishes the efficacy of novel compounds in protection of the nigrostriatum in a pre-clinical mouse model of Parkinson's disease.</p

Can the weakening of Indian Monsoon be attributed to anthropogenic aerosols?

Abstract Literature found that the increasing concentration of Anthropogenic Aerosol (AA) is the key reason behind the weakening trend of Indian Summer Monsoon Rainfall (ISMR), based on the Coupled Model Intercomparison Project Phase5 (CMIP5) simulations with AA-only forcing. Here, we re-examine and find that AA-only simulations show country-wide drying, in contrast to the observed east-west asymmetry in the recent ISMR trend. For further evaluation, we decompose the changes in moisture convergence during summer monsoon into dynamic and thermodynamic components. We find that multi-run ensemble averages for individual CMIP5 models do not capture the observed dominance of the changes in dynamic component over the thermodynamic one. An optimal fingerprinting technique for detection and attribution also fail to attribute the changes in ISMR to AA, either because of large internal variability and/or intermodel spread. This implies the need for more careful assessment of AA-only simulations for the ISMR before attributing the changes to AA.</jats:p