Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. Neuronal degeneration is accompanied by primarily oligodendrocytic accumulation of ␣-synuclein (␣syn) as opposed to the neuronal inclusions more commonly found in other ␣-synucleinopathies such as Parkinson's disease. It is unclear how ␣syn accumulation in oligodendrocytes may lead to the extensive neurodegeneration observed in MSA; we hypothesize that the altered expression of oligodendrocyte-derived neurotrophic factors by ␣syn may be involved. In this context, the expression of a number neurotrophic factors reportedly expressed by oligodendrocytes [glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor 1 (IGF-1), as well as basic fibroblast growth factor 2 (bFGF2), reportedly astrocyte derived] were examined in transgenic mouse models expressing human ␣syn (h␣syn) under the control of either neuronal (PDGF␤ or mThy1) or oligodendrocytic (MBP) promoters. Although protein levels of BDNF and IGF-1 were altered in all the ␣syn transgenic mice regardless of promoter type, a specific decrease in GDNF protein expression was observed in the MBP-h␣syn transgenic mice. Intracerebroventricular infusion of GDNF improved behavioral deficits and ameliorated neurodegenerative pathology in the MBP-h␣syn transgenic mice. Consistent with the studies in the MBP-h␣syn transgenic mice, analysis of GDNF expression levels in human MSA samples demonstrated a decrease in the white frontal cortex and to a lesser degree in the cerebellum compared with controls. These results suggest a mechanism in which ␣syn expression in oligodendrocytes impacts on the trophic support provided by these cells for neurons, perhaps contributing to neurodegeneration.

Background & Objectives Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 “transcriptome” is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer’s disease and type-2 diabetes. Conclusion Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.

MicroRNA (miRNA) are short sequences of RNA that function as post-transcriptional regulators by binding to target mRNA transcripts resulting in translational repression. A number of recent studies have identified miRNA as being involved in neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, the role of miRNA in Multiple System Atrophy (MSA), a progressive neurodegenerative disorder characterized by oligodendroglial accumulation of alpha-synuclein remains unexamined. In this context, this study examined miRNA profiles in MSA cases compared to controls and in transgenic (tg) models of MSA compared to non tg mice. The results demonstrate a widespread dysregulation of miRNA in MSA cases, which is recapitulated in the murine models. The study employed a cross-disease, cross-species approach to identify miRNA that were either specifically dysregulated in MSA or were commonly dysregulated in neurodegenerative conditions such as AD, Dementia with Lewy bodies, Progressive Supranuclear Palsy and Corticobasal Degeneration or the tg mouse model equivalents of these disorders. Using this approach we identified a number of miRNA that were commonly dysregulated between disorders and those that were disease-specific. Moreover, we identified miR-96 as being up regulated in MSA. Consistent with the up regulation of miR-96, mRNA and protein levels of members of the solute carrier protein family SLC1A1 and SLC6A6, miR-96 target genes, were down regulated in MSA cases and a tg model of MSA. These results suggest that miR-96 dysregulation may play a role in MSA and its target genes may be involved in the pathogenesis of MSA.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by autonomic failure, parkinsonism, cerebellar ataxia, and oligodendrocytic accumulation of alphasynuclein (αsyn). Oxidative stress has been linked to neuronal death in MSA and the mitochondrial toxin 3-nitropropionic acid (3NP) is known to enhance the motor deficits and neurodegeneration in transgenic mice models of MSA. However, the effect of 3NP administration on αsyn itself has not been studied. In this context, we examined the neuropathological effects of 3NP administration in αsyn transgenic mice expressing human αsyn (hαsyn) under the control of the myelin basic protein (MBP) promoter and the effect of this administration on posttranslational modifications of αsyn, on levels of total αsyn, and on its solubility. We demonstrate that 3NP administration altered levels of nitrated and oxidized αsyn in the MBP-hαsyn tg while not affecting global levels of phosphorylated or total αsyn. 3NP administration also exaggerated neurological deficits in the MBP-hαsyn tg mice, resulting in widespread neuronal degeneration and behavioral impairment. Keywords behavior; oligodendrocytes; synucleinopathyMultiple system atrophy (MSA) is a sporadic neurodegenerative disease of the central and autonomic nervous system. Cardinal clinical features include autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs (Wenning et al., 2004). Pathologically, MSA is primarily characterized by alpha-synuclein (αsyn)-positive glial cytoplasmic inclusions, although αsyn inclusions in neurons have also been reported. Neuronal loss, predominantly in the basal ganglia, brain stem, and cerebellum is also a key pathological feature of MSA (Burn and Jaros, 2001). Currently there are no therapeutic treatments for MSA, and although patients are * Correspondence to: Eliezer Masliah, Department of Neurosciences, University of California-San Diego, La Jolla, CA 92093-0624. emasliah@ucsd.edu. The first two authors contributed equally to this work. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript prescribed drugs to manage the symptoms of MSA, these do nothing to halt the progression of the disease or tackle the underlying cause.Although the exact mechanisms underlying the abnormal accumulation and aggregation of αsyn in MSA remain unclear, evidence from case-control epidemiological studies suggests that occupational exposure to pesticides, insecticides, or chemicals interfering with the mitochondrial electron transport chain may be associated with increased risk of MSA (Hanna et al., 1999;Nee et al., 1991;Vanacore et al., 2005). In animal studies, chronic administration of 3-nitropropionic acid (3NP), an environmental toxin that inhibits mitochondrial complex II function, has been reported to mimic MSA (Stefanova et al., 2005b). Furthermore, high doses of 3NP, although eventually leading to significant mortality in treated mice, have been demonstrated to aggravate nigrostriatal and olivopontocerebella...

The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine adminstration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine adminstration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine adminstration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders.

Neutrophils traffic to the lungs in large numbers during influenza virus infection. Although the ability of these cells to respond to numerous chemotactic stimuli has been described in other systems, the chemokine receptors mediating recruitment of neutrophils to the lungs during influenza virus infection and the role of this cell type in viral clearance are currently undefined. In the present study, we used CXCR2(/) mice to investigate the role of the chemokine receptor CXCR2 in neutrophil recruitment to the lungs during influenza virus infection and to determine the role of neutrophils in viral clearance. We infected CXCR2(/) or wild-type mice with influenza and assessed the level of inflammation, the cellular composition of the inflammatory infiltrate, and viral titers in the lungs. Absence of CXCR2 ablated neutrophil recruitment to the lungs, but had no effect on peak viral titers or on the kinetics of viral clearance. Thus, it appears that CXCR2 is the major receptor mediating neutrophil trafficking to the lung during influenza virus infection, but that neutrophils do not play an essential role in viral clearance.

Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro-nerve growth factor (NGF), NGF, brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro-NGF were increased in saline-treated hAPP tg mice. In contrast, CBL-treated hAPP tg mice showed levels of pro-NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL-treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75(NTR) immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline-treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons.

Influenza virus infections induce chemokines and cytokines, which regulate the immune response. The chemokine receptor CCR2 plays an important role in macrophage recruitment and in the development of T1 immunity. In the present study, we addressed the role of CCR2 in influenza A virus infection. CCR2 knockout (؊/؊) mice are protected against influenza A virus infection, despite delayed recruitment of macrophages. We show that low-dose influenza infection of CCR2؊/؊ mice leads to increased neutrophilia between Days 5 and 10 after infection and decreased monocyte/macrophage and CD4 ؉ T cell recruitment to the lungs between Days 5 and 7 after infection. These changes in leukocyte recruitment did not result from or cause increased viral titers or delayed viral clearance. Neutrophilia in the lungs correlated with increased keratinocyte-derived chemokine (KC) and/or MIP-2 expression in CCR2؊/؊ mice between Days 5 to 10 after infection, although the kinetics of neutrophil recruitment was not altered. MIP-2 mRNA and protein expression was increased three-to fivefold, and KC protein levels were increased two-to threefold in CCR2؊/؊ compared with CCR2 wild-type mice at Day 5 after infection. This preceded the peak neutrophil influx, which occurred 7 days after infection. In vitro studies confirmed that MIP-2 and KC accounted for neutrophil chemotactic activity in the bronchoalveolar lavage. CCR2 deficiency also resulted in increased MIP-1␣, MIP-1␤, MCP-1, and IFN-inducible protein 10 and decreased RANTES mRNA expression. Furthermore, IL-6 and TNF-␣ cytokine production were elevated after infection. These studies suggest that CCR2 plays a multifactorial role in the development of the immune response to influenza. J. Leukoc. Biol. 81: 793-801; 2007.