Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-penetrating peptides (CPPs), such as the one derived from the human immunodeficiency virus Tat protein, facilitate the delivery of cargoes across cellular membranes. However, questions about the therapeutic potential of CPP-mediated delivery remain. For instance, the impact of the purification procedure on the functionality of Tat-fusion proteins has not been systematically examined. Here, we isolated fusion proteins of the chaperone heat shock protein 70 (Hsp70) and the Tat CPP under denaturing or native conditions. To investigate the therapeutic potential of different recombinant protein preparations, we examined Tat-Hsp70 transduction efficiency and quantified Tat-Hsp70-mediated folding of a chaperone-dependent yellow fluorescent protein in vitro. Transduction efficiency and chaperone activity of Tat-Hsp70-treated cells was significantly higher compared to cells treated with Hsp70. The application of native isolated Tat-Hsp70 had the strongest effect. This chaperone activity correlates with increased viability of cells treated with the recombinant protein after cell death induction with 6-hydroxydopamine. This suggests that the method of recombinant Tat-fusion protein purification influences its functionality. For Tat-Hsp70, the method of choice seems to be isolation under native conditions, for which we present a purification protocol. Our results may contribute to improve Tat-fusion protein application in basic research and may facilitate its use as therapeutic tool, for instance in Parkinson's disease.
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PMID:Quantitative evaluation of chaperone activity and neuroprotection by different preparations of a cell-penetrating Hsp70. 1845 3

Over the last 2 decades, numerous innate inflammatory mediators have been reported to be upregulated in pathologically vulnerable regions of the brain in Alzheimer's disease (AD). These data have led to a reexamination of the dogma of brain immunologic privilege and to new studies that examine the role of the innate inflammatory response in a number of other neurologic disorders, particularly Parkinson's disease and human immunodeficiency virus dementia. In addition, basic science discoveries about neuroinflammation are now beginning to move to the clinic. More than 20 epidemiologic surveys have consistently demonstrated that common non-steroidal anti-inflammatory drugs may protect against the development of AD. By contrast, anti-inflammatory treatment trials for existing AD have typically shown little to no effect on halting or reversing the disorder, although the agents tested have often been at odds with those suggested by the epidemiologic and basic science results. The extensive literature on innate inflammation and neurologic disease notwithstanding, three fundamental questions still remain to be answered fully. First, are innate inflammatory responses a cause of neurologic disease or merely a more sophisticated means than previously imagined for removing the detritus left by more primary pathogenic mechanisms? Second, can anti-inflammatory agents effectively treat existing neurologic disease, or is a protective strategy in high-risk patients the only reasonable option? Third, whether for protection or treatment, what is the best choice of anti-inflammatory agent given the basic science mechanisms and epidemiologic results that have been reported?
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PMID:The inflammatory response in Alzheimer's disease. 1867 8

The membrane transporter multi-drug resistance 1 (MDR1, P-gp) regulates the bioavailability of endogenous and exogenous compounds and has been implicated in disorders such as Parkinson's disease, cancer, epilepsy, human immunodeficiency virus disease, and inflammatory bowel disease. To promote further understanding of the role of MDR1 in disease, we have characterized cellular MDR1 mRNA expression in post-mortem human and fresh-frozen Sprague-Dawley rat tissues by using radioactive oligonucleotide probe in situ hybridization. We report MDR1 mRNA in human and rat endothelial cells of small vessels in the brain and pia mater. Mdr1 mRNA is also expressed in the blood vessel walls of rat sensory dorsal root and sympathetic ganglia. In peripheral tissues, we have observed MDR1 mRNA in human and rat liver and renal tubules and in human adrenal cortex and the epithelial lining of rat intestine. In female and male reproductive tissues of rat, strong gene activity has been found in steroid-hormone-synthesizing cells. Quantification of MDR1 mRNA in human striatum has revealed reduced levels in Parkinson patients compared with control individuals. The high expression of MDR1 mRNA in blood vessels of the nervous system, in tissues involved in absorption and excretion, and in tissues forming barriers to the environment support the physiological role of MDR1 as a regulator of intracellular levels of endogenous and exogenous compounds.
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PMID:Expression of multi-drug resistance 1 mRNA in human and rodent tissues: reduced levels in Parkinson patients. 1885 17

The phenotype of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) in the developed world has changed with the broad institution of highly active antiretroviral therapy (HAART) and with aging of the HIV+ population. Extrapyramidal motor signs were a prominent feature of HAND as defined in the early stages of the epidemic but has not been reevaluated in the era of HAART. Moreover, the contribution of aging to extrapyramidal motor signs in the context of HIV remains undefined. We examined these questions among the 229 HIV+ participants in the Hawaii Aging with HIV Cohort compared to age-, gender-, and ethnicity-matched HIV-negative controls. Extrapyramidal motor signs were quantified using the motor exam of the Unified Parkinson's Disease Rating Scale (UPDRSmotor) and compared to concurrent neuropsychological and clinical cognitive diagnostic categorization. The mean UPDRSmotor score increased with older age (1.68 versus 3.35; P<.001) and with HIV status (1.18 versus 3.56; P<.001). Age group (P=.024), HIV status (P<.001), and the interaction between age and HIV (P=.026) were significantly associated with UPDRSmotor score. Among HIV+ patients, the mean UPDRSmotor score increased with worsening cognitive diagnostic category (P<.001) where it was 2.06 (2.31) in normal cognition (n=110), 3.21 (3.48) in minor cognitive motor disorder (MCMD) (n=84), and 5.72 (5.01) in HIV-associated dementia (HAD) (n=37). We conclude that extrapyramidal motor signs are increased in HIV in the era of HAART and that the impact of HIV on extrapyramidal motor signs is exacerbated by aging. These results highlight the importance of a careful neurological examination in the evaluation of HIV patients.
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PMID:Aging exacerbates extrapyramidal motor signs in the era of highly active antiretroviral therapy. 1898 14

Vectors based on non-HIV lentiviruses are opening up new approaches for the treatment of human disorders. These vectors efficiently deliver genes into many different types of cells from a broad range of species including man and the resulting gene expression is long-term. These features make them very attractive to be transformed into tools for gene therapy. HIV-1 based lentiviral vectors were initially developed, a process which provided valuable insights into the biology of these vectors allowing progressive improvement of non-HIV vectors. The latest vectors have been refined to a very high level and can be produced safely for the clinic. This review will describe the general features of lentiviral vectors with particular emphasis on vectors derived from the non-HIV lentiviruses such as equine infectious anaemia virus (EIAV), simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV). It will then describe some key examples of gene therapy applications in neurological diseases such as Parkinson's disease (PD), motor neuron diseases, lysosomal storage diseases and ocular disorders. Finally, the prospects for clinical application of non-HIV lentiviral vectors for these disorders will also be outlined.
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PMID:Development and applications of non-HIV-based lentiviral vectors in neurological disorders. 1907 24

Dopaminergic dysfunction is thought to play a pivotal role in human immunodeficiency virus (HIV)-related dementia. Decreased dopamine (DA) levels in the cerebrospinal fluid (CSF) and neuronal loss in the substantia nigra (SN) have been reported in HIV-infected patients, suggesting nigrostriatal damage. Structural changes detectable as hyperechogenicity in transcranial ultrasound (TCS) scans of the SN have been reported in patients with Parkinson's disease (PD) and other neurological conditions. In this study, we assessed the echomorphology of the SN in 40 HIV-positive patients compared to 40 age- and sex-matched healthy controls and correlated these findings with CSF levels of DA and the metabolites homovanillic acid (HVA) and 3,4-dihydroxy phenylacetic acid (DOPAC) and with neuropsychologic performance. We observed that the SN of HIV-infected patients was hyperechogenic relative to that of controls (0.07 +/- 0.05 vs. 0.04 +/- 0.07 cm(2); mean +/- SEM; P < 0.001) and that this SN hyperechogenicity was correlated with decreased DA levels in the CSF, decreased CD4 cell count, and an impaired performance in the psychopathology assessment scale (AMDP) subtest for drive and psychomobility. An association to CDC stage, duration of HIV infection, or presence of HIV dementia was not observed. Our results indicate changes in the nigrostriatal system in HIV-infected patients that are detectable as hyperechogenic SN precede prominent extrapyramidal symptoms and cognitive dysfunction.
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PMID:Substantia nigra hyperechogenicity and CSF dopamine depletion in HIV. 1924 Sep 51

Microglial inflammatory responses affect Parkinson's disease (PD) associated nigrostriatal degeneration. This is triggered, in measure, by misfolded, nitrated alpha-synuclein (N-alpha-syn) contained within Lewy bodies that are released from dying or dead dopaminergic neurons into the extravascular space. N-alpha-syn-stimulated microglial immunity is regulated by CD4+ T cell subset. Indeed, CD4+CD25+ regulatory T cells (Treg) induce neuroprotective immune responses. This is seen in rodent models of stroke, amyotrophic lateral sclerosis, human immunodeficiency virus associated neurocognitive disorders, and PD. To elucidate the mechanism for Treg-mediated microglial neuroregulatory responses, we used a proteomic platform integrating difference gel electrophoresis and tandem mass spectrometry peptide sequencing. These tests served to determine consequences of Treg on the N-alpha-syn stimulated microglia. The data demonstrated that Treg substantially alter the microglial proteome in response to N-alpha-syn. This is seen through Treg abilities to suppress microglial proteins linked to cell metabolism, migration, protein transport and degradation, redox biology, cytoskeletal, and bioenergetic activities. We conclude that Treg modulate the N-alpha-syn microglial proteome and, in this way, can slow the tempo and course of PD.
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PMID:Proteomic studies of nitrated alpha-synuclein microglia regulation by CD4+CD25+ T cells. 1943

While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as "immune privilege," it is now clear that immune responses do occur in the CNS-giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.
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PMID:CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? 1966 92

Increasing evidence suggests that apoptosis may be the mechanism underlying cell death in selective loss of nigral dopaminergic neurons in Parkinson's disease (PD). Previous studies strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway has a critical role in the animal model with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. In this study, we report the inhibitory effect of a peptide designated as Tat-JBD on JNKs activation. The sequence of Tat is corresponding to the cell-membrane transduction domain of human immunodeficiency virus-type 1 (HIV-1) and the sequence of an 11-amino acid peptide is corresponding to the residues of JNK-binding domain (JBD) on JNK-interacting protein-1 (JIP-1). Tat-JBD is confirmed to perturb the assembly of JIP-1-JNKs complex, inhibit the activation of JNKs induced by MPTP and consequently diminish the phosphorylation of c-Jun. It also inhibits the phosphorylation of Bcl-2 and the releasing of Bax from Bcl-2/Bax dimmers, sequentially attenuates the translocation of Bax to mitochondria, the release of cytochrome c, the activation of caspase3 and the hydrolyzation of poly-ADP-ribose-polymerase. The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by infusion of the peptide Tat-JBD in MPTP-treated mice. Our findings imply that Tat-JBD offers neuroprotection against MPTP injury via inhibiting the JNK-signaling pathway, and may provide a promising therapeutic approach for PD.
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PMID:Small peptide inhibitor of JNKs protects against MPTP-induced nigral dopaminergic injury via inhibiting the JNK-signaling pathway. 2001 Aug 51

Castleman disease is a quite uncommon lymphoproliferative disorder usually occurring in the lymph nodes. Rarely, Castleman disease develops in an extranodal anatomic location. We report on the first biopsy-proven case of multicentric plasma cell type of Castleman disease involving the orbital areas in a human herpes virus 8 (HHV-8)-unassociated/ human immunodeficiency virus (HIV)-seronegative 70-year-old man suffering from Parkinson disease. The diagnosis was established on the basis of morphologic, immunophenotypic, and molecular findings of a lymph node and orbital soft tissue biopsy. We additionally provide a review of all previously published cases of Castleman disease with an orbital involvement, discussing the distinctive characteristics and potential associations with regard to their counterparts at other sites. Although Castleman disease involving the orbit is an exceptionally rare occurrence that may present initially with ocular signs and symptoms, this should be included in the complete differential diagnosis of orbital mass lesion.
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PMID:Orbital involvement in Castleman disease. 2007 Sep 98


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