Publications by authors named "Preeti Khandelwal"

12 Publications

  • Page 1 of 1

Aromatase activity in brain and ovary: seasonal variations correlated with circannual gonadal cycle in the catfish, Heteropneustes fossilis.

Indian J Exp Biol 2014 May;52(5):527-37

Seasonal variations in the aromatase activity in H. fossilis estimated by a microassay were correlated with the sex steroids, vitellogenin in and ovarian weight during circannual reproductive cycle. In the female catfish, aromatase activity was detectable in the hypothalamus throughout the year whereas in ovary only during active vitellogenesis. In the catfish, hypothalamic aromatase levels increased two times during annual gonadal cycle, once in a fully gravid fish and then in a reproductively quiescent fish. On the other hand, increase in the ovarian aromatase activity was observed only during vitellogenesis, which showed a direct correlation with plasma levels of sex steroids. Further, plasma levels of testosterone and estradiol suggested a precursor-product relationship. At the completion of vitellogenesis, ovarian aromatase activity declined sharply resulting in elevation of plasma testosterone levels, which in turn could be utilized as substrate by the hypothalamic aromatase whose activity was the highest in the postvitellogenic catfish. At least two isoforms of gene, cyp19a and cyp19b, coding for aromatase in ovary and brain respectively were expressed in the catfish. Aromatase activity was more concentrated in those areas of catfish brain, which have been implicated in the control of reproduction.
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May 2014

Wild type TDP-43 induces neuro-inflammation and alters APP metabolism in lentiviral gene transfer models.

Exp Neurol 2012 May 28;235(1):297-305. Epub 2012 Feb 28.

Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA.

The transactivation DNA-binding protein (TDP-43) pathology is associated with fronto-temporal lobar dementia (FTLD) with ubiquitinated inclusions and some cases of Alzheimer's disease (AD). Proteolytic fragments of β-amyloid precursor protein (βAPP) are detected in AD as well as the cerebrospinal fluid (CSF) from FTLD and Amyotrophic Lateral Sclerosis (ALS) patients, suggesting alteration in APP processing. Because of the overlap in TDP-43 pathology between FTLD and AD, we sought to determine whether there is a relationship between TDP-43 and APP metabolism. We generated gene transfer models using lentiviral delivery of human TDP-43 and Aβ(1-42) into the rat primary motor cortex and examined their role 2 weeks post-injection. Expression of TDP-43 and/or Aβ(1-42) increase pro-inflammatory markers, including Interleukin (IL)-6, tumor necrosis factor (TNF-α), glial neurofibrillary proteins (GFAP) and ionized calcium binding adaptor molecule 1 (IBA-1). Lentiviral Aβ(1-42) up-regulates endogenous TDP-43 and promotes its phosphorylation, aggregation and cleavage into 35 kDa fragments. Inversely, lentiviral TDP-43 expression increases the levels and activity of β-secretase (BACE), accelerating production of APP C-terminal fragments (C99) and Aβ(1-40). Here we show that TDP-43 up-regulates APP metabolism and suggest a mechanistic link between TDP-43 and BACE.
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http://dx.doi.org/10.1016/j.expneurol.2012.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434705PMC
May 2012

Drosophila lilliputian is required for proneural gene expression in retinal development.

Dev Dyn 2012 Mar 25;241(3):553-62. Epub 2012 Jan 25.

Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104, USA.

Background: Proper neurogenesis in the developing Drosophila retina requires the regulated expression of the basic helix-loop-helix (bHLH) proneural transcription factors Atonal (Ato) and Daughterless (Da). Factors that control the timing and spatial expression of these bHLH proneural genes in the retina are required for the proper formation and function of the adult eye and nervous system.

Results: Here we report that lilliputian (lilli), the Drosophila homolog of the FMR2/AF4 family of proteins, regulates the transcription of ato and da in the developing fly retina. We find that lilli controls ato expression at multiple enhancer elements. We also find that lilli contributes to ato auto-regulation in the morphogenetic furrow by first regulating the expression of da prior to ato. We show that FMR2 regulates the ato and da homologs MATH5 and TCF12 in human cells, suggesting a conservation of this regulation from flies to humans.

Conclusions: We conclude that lilliputian is part of the genetic program that regulates the expression of proneural genes in the developing retina.
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http://dx.doi.org/10.1002/dvdy.23738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946344PMC
March 2012

Wild type and P301L mutant Tau promote neuro-inflammation and α-Synuclein accumulation in lentiviral gene delivery models.

Mol Cell Neurosci 2012 Jan 14;49(1):44-53. Epub 2011 Sep 14.

Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA.

Neurodegeneration involves multiple pathogenic proteins, including Tau, Aβ, TDP-43 and α-Synuclein, but there is little information how these pathogenic proteins interact. We cloned human wild type 4 repeat Tau (Tau(wt)) and mutant Tau(P301L) into a lentivirus and performed stereotaxic injection into the rat motor cortex to examine Tau modification, neuro-inflammation and changes of other proteins associated with neurodegeneration. Tau(P301L) was associated with more phosphorylation of Tau, including Thr 181 and Ser 262 residues and resulted in more aggregation. Both forms of Tau expression increased glycogen synthase kinase-3 (GSK-3) activity, polo-like kinase-2 (PLK2) levels and decreased protein phosphatase activity, but had no effects on casein kinase-1 (CK1). No changes were observed in glial fibrillary acidic protein (GFAP) staining with either Tau(wt) or Tau(P301L), but both caused microglial changes and higher interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels. Tau(wt) and Tau(P301L) increased the levels of endogenous α-Synuclein, but not β-amyloid precursor protein (βAPP) or Tar-DNA binding protein (TDP-43). The levels of phosphorylated Ser-129 α-Synuclein (p-Ser129) were also increased with Tau(wt) and Tau(P301L) expressing animals. These data suggest that Tau(wt) and Tau(P301L) alter kinase activities, but they differentially induce inflammation, Tau modification and α-Synuclein phosphorylation. This change of α-Synuclein in Tau gene transfer models suggests that Tau pathology may lead to α-Synuclein modification in neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.mcn.2011.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246111PMC
January 2012

Inflammation in the early stages of neurodegenerative pathology.

J Neuroimmunol 2011 Sep 5;238(1-2):1-11. Epub 2011 Aug 5.

Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA.

Inflammation is secondary to protein accumulation in neurodegenerative diseases, including Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis. Emerging evidence indicate sustained inflammatory responses, involving microglia and astrocytes in animal models of neurodegeneration. It is unknown whether inflammation is beneficial or detrimental to disease progression and how inflammatory responses are induced within the CNS. Persistence of an inflammatory stimulus or failure to resolve sustained inflammation can result in pathology, thus, mechanisms that counteract inflammation are indispensable. Here we review studies on inflammation mediated by innate and adaptive immunity in the early stages of neurodegeneration and highlight important areas for future investigation.
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http://dx.doi.org/10.1016/j.jneuroim.2011.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176984PMC
September 2011

Characterization of a Drosophila Alzheimer's disease model: pharmacological rescue of cognitive defects.

PLoS One 2011 6;6(6):e20799. Epub 2011 Jun 6.

Department of Biology, Drexel University, Philadelphia, Pennsylvania, United States of America.

Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Aβ(40) and Aβ(42), the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a γ-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020799PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108982PMC
September 2011

Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models.

Hum Mol Genet 2011 Jun 4;20(11):2091-102. Epub 2011 Mar 4.

Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA.

Intraneuronal amyloid-β (Aβ) may contribute to extracellular plaque deposition, the characteristic pathology of Alzheimer's disease (AD). The E3-ubiquitin ligase parkin ubiquitinates intracellular proteins and induces mitophagy. We previously demonstrated that parkin reduces Aβ levels in lentiviral models of intracellular Aβ. Here we used a triple transgenic AD (3xTg-AD) mouse, which over-expresses APP(Swe), Tau(P301L) and harbor the PS1(M146V) knock-in mutation and found that lentiviral parkin ubiquitinated intracellular Aβ in vivo, stimulated beclin-dependent molecular cascade of autophagy and facilitated clearance of vesicles containing debris and defective mitochondria. Parkin expression decreased intracellular Aβ levels and extracellular plaque deposition. Parkin expression also attenuated caspase activity, prevented mitochondrial dysfunction and oxidative stress and restored neurotransmitter synthesis. Restoration of glutamate synthesis, which was independent of glial-neuronal recycling, depended on mitochondrial activity and led to an increase in γ-amino butyric acid levels. These data indicate that parkin may be used as an alternative strategy to reduce Aβ levels and enhance autophagic clearance of Aβ-induced defects in AD. Parkin-mediated clearance of ubiquitinated Aβ may act in parallel with autophagy to clear molecular debris and defective mitochondria and restore neurotransmitter balance.
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http://dx.doi.org/10.1093/hmg/ddr091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090189PMC
June 2011

β-amyloid triggers ALS-associated TDP-43 pathology in AD models.

Brain Res 2011 Apr 2;1386:191-9. Epub 2011 Mar 2.

Department of Biochemistry Molecular and Cell Biology, Georgetown University Medical Center, Washington, DC 20007, USA.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with loss of motor neurons in the brain and spinal cord. ALS is occasionally diagnosed with frontotemporal lobar dementia with ubiquitin-positive inclusions (FTLD-U). Alzheimer's disease (AD) is the most common type of age-associated dementia. Abnormal levels of aggregated Tar-DNA binding protein-43 (TDP-43) are detected in the majority of patients with ALS, FTLD and AD. We observed a significant increase (200%) in the levels of TDP-43 in cortical autopsies of late stage AD patients. Lentiviral expression of Aβ(1-42) in the rat motor cortex led to an increase in TDP-43 pathology, including up-regulation of the mature ~44kDa protein, identical to the pathological changes seen in AD. Furthermore, expression of Aβ(1-42) was associated with TDP-43 phosphorylation and accumulation in the cytosol. Clearance of Aβ with parkin prevented TDP-43 pathology. TDP-43 modifications were also observed in 3xTransgenic AD (3xTg-AD) compared to wild type mice, but these changes were attenuated in parkin-injected hippocampi, even in the presence of Tau pathology, suggesting that TDP-43 pathology is triggered by Aβ, independent of Tau. Increased levels of casein kinase (CK1 and CK2), which are associated with TDP-43 phosphorylation, were also observed in Aβ(1-42) expressing brains. These data indicate an overlap in TDP-43 pathology between AD and ALS-FTLD and suggest that Aβ triggers modifications of TDP-43.
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http://dx.doi.org/10.1016/j.brainres.2011.02.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073036PMC
April 2011

Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model.

Mol Neurodegener 2010 Nov 4;5:47. Epub 2010 Nov 4.

Department of Neuroscience, Georgetown University Medical Center, Washington D,C, U,S,A, 20007.

Background: α-Synuclein aggregates in Lewy bodies and plays a central role in the pathogenesis of a group of neurodegenerative disorders, known as "Synucleinopathies", including Parkinson's disease. Parkin mutations result in loss of parkin E3-ubiquitin ligase activity and cause autosomal recessive early onset parkinsonism.

Results: We tested how these two genes interact by examining the effects of parkin on post-translational modification of α-Synuclein in gene transfer animal models, using a lentiviral gene delivery system into the striatum of 2-month old male Sprague Dawley rats.Viral expression of wild type α-Synuclein caused accumulation of α-Synuclein and was associated with increased cell death and inflammation. α-Synuclein increased PLK2 levels and GSK-3β activity and increased the levels of phosphorylated α-Synuclein and Tau. Parkin co-expression reduced the levels of phosphorylated α-Synuclein and attenuated cell death and inflammation. Parkin reduced PLK2 levels and increased PP2A activation.

Conclusions: These data suggest that parkin reduces α-Synuclein levels and alters the balance between phosphatase and kinase activities that affect the levels of phosphorylated α-Synuclein. These results indicate novel mechanisms for parkin protection against α-Synuclein-induced toxicity in PD.
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http://dx.doi.org/10.1186/1750-1326-5-47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987994PMC
November 2010

The Relationship between Parkin and Protein Aggregation in Neurodegenerative Diseases.

Front Psychiatry 2010 3;1:15. Epub 2010 Jun 3.

Department of Neuroscience, Georgetown University Medical Center Washington, DC, USA.

The most prominent changes in neurodegenerative diseases are protein accumulation and inclusion formation. Several neurodegenerative diseases, including Alzheimer's, the Synucleinopathies and Tauopathies share several overlapping clinical symptoms manifest in Parkinsonism, cognitive decline and dementia. As degeneration progresses in the disease process, clinical symptoms suggest convergent pathological pathways. Biochemically, protein cleavage, ubiquitination and phosphorylation seem to play fundamental roles in protein aggregation, inclusion formation and inflammatory responses. In the following we provide a synopsis of the current knowledge about protein accumulation and astrogliosis as a common denominator in neurodegenerative diseases, and we propose insights into protein degradation and anti-inflammation. We review the E3-ubiquitin ligase and other possible functions of parkin as a suppressant of inflammatory signs and a strategy to clear amyloid proteins in neurodegenerative diseases.
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http://dx.doi.org/10.3389/fpsyt.2010.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059628PMC
November 2011

Characterization of human lysophospholipid acyltransferase 3.

J Lipid Res 2009 Aug 7;50(8):1563-70. Epub 2009 Apr 7.

Department of Biology, Drexel University, Philadelphia, PA 19104, USA.

Esterifying lysophospholipids may serve a variety of functions, including phospholipid remodeling and limiting the abundance of bioactive lipids. Recently, a yeast enzyme, Lpt1p, that esterifies an array of lysophospholipids was identified. Described here is the characterization of a human homolog of LPT1 that we have called lysophosphatidylcholine acyltransferase 3 (LPCAT3). Expression of LPCAT3 in Sf9 insect cells conferred robust esterification of lysophosphatidylcholine in vitro. Kinetic analysis found apparent cooperativity with a saturated acyl-CoA having the lowest K0.5 (5 microM), a monounsaturated acyl-CoA having the highest apparent Vmax (759 nmol/min/mg), and two polyunsaturated acyl-CoAs showing intermediate values. Lysophosphatidylethanolamine and lysophosphatidylserine were also utilized as substrates. Electrospray ionization mass spectrometric analysis of phospholipids in Sf9 cells expressing LPCAT3 showed a relative increase in phosphatidylcholine containing saturated acyl chains and a decrease in phosphatidylcholine containing unsaturated acyl chains. Targeted reduction of LPCAT3 expression in HEK293 cells had essentially an opposite effect, resulting in decreased abundance of saturated phospholipid species and more unsaturated species. Reduced LPCAT3 expression resulted in more apoptosis and distinctly fewer lamellipodia, suggesting a necessary role for lysophospholipid esterification in maintaining cellular function and structure.
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http://dx.doi.org/10.1194/jlr.M800398-JLR200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724057PMC
August 2009

An AICD-based functional screen to identify APP metabolism regulators.

Mol Neurodegener 2007 Aug 24;2:15. Epub 2007 Aug 24.

Department of Bioscience & Biotechnology, Drexel University, Philadelphia, PA, USA.

Background: A central event in Alzheimer's disease (AD) is the regulated intramembraneous proteolysis of the beta-amyloid precursor protein (APP), to generate the beta-amyloid (Abeta) peptide and the APP intracellular domain (AICD). Abeta is the major component of amyloid plaques and AICD displays transcriptional activation properties. We have taken advantage of AICD transactivation properties to develop a genetic screen to identify regulators of APP metabolism. This screen relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4. Production of AICD-Gal4 induces Gal4-UAS driven luciferase expression. Therefore, when regulators of APP metabolism are modulated, luciferase expression is altered.

Results: To validate this experimental approach we modulated alpha-, beta-, and gamma-secretase levels and activities. Changes in AICD-Gal4 levels as measured by Western blot analysis were strongly and significantly correlated to the observed changes in AICD-Gal4 mediated luciferase activity. To determine if a known regulator of APP trafficking/maturation and Presenilin1 endoproteolysis could be detected using the AICD-Gal4 mediated luciferase assay, we knocked-down Ubiquilin 1 and observed decreased luciferase activity. We confirmed that Ubiquilin 1 modulated AICD-Gal4 levels by Western blot analysis and also observed that Ubiquilin 1 modulated total APP levels, the ratio of mature to immature APP, as well as PS1 endoproteolysis.

Conclusion: Taken together, we have shown that this screen can identify known APP metabolism regulators that control proteolysis, intracellular trafficking, maturation and levels of APP and its proteolytic products. We demonstrate for the first time that Ubiquilin 1 regulates APP metabolism in the human neuroblastoma cell line, SH-SY5Y.
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http://dx.doi.org/10.1186/1750-1326-2-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2071909PMC
August 2007