Dopamine (DA) neurons in sporadic Parkinson disease (PD) display dysregulated gene expression networks and signaling pathways that are implicated in PD pathogenesis. Micro (mi)RNAs are regulators of gene expression, which could be involved in neurodegenerative diseases. We determined the miRNA profiles in laser microdissected DA neurons from postmortem sporadic PD patients’ brains and age-matched controls. DA neurons had a distinctive miRNA signature and a set of miRNAs was dysregulated in PD. Bioinformatics analysis provided evidence for correlations of miRNAs with signaling pathways relevant to PD, including an association of miR-126 with insulin/IGF-1/PI3K signaling. In DA neuronal cell systems, enhanced expression of miR-126 impaired IGF-1 signaling and increased vulnerability to the neurotoxin 6-OHDA by downregulating factors in IGF-1/PI3K signaling, including its targets p85β, IRS-1, and SPRED1. Blocking of miR-126 function increased IGF-1 trophism and neuroprotection to 6-OHDA. Our data imply that elevated levels of miR-126 may play a functional role in DA neurons and in PD pathogenesis by downregulating IGF-1/PI3K/AKT signaling and that its inhibition could be a mechanism of neuroprotection.
In patients with Huntington's disease (HD), the proteolytic activity of the ubiquitin proteasome system (UPS) is reduced in the brain and other tissues. The pathological hallmark of HD is the intraneuronal nuclear protein aggregates of mutant huntingtin. We determined how to enhance UPS function and influence catalytic protein degradation and cell survival in HD. Proteasome activators involved in either the ubiquitinated or the non-ubiquitinated proteolysis were overexpressed in HD patients' skin fibroblasts or mutant huntingtin-expressing striatal neurons. Following compromise of the UPS, overexpression of the proteasome activator subunit PA28γ, but not subunit S5a, recovered proteasome function in the HD cells. PA28γ also improved cell viability in mutant huntingtin-expressing striatal neurons exposed to pathological stressors, such as the excitotoxin quinolinic acid and the reversible proteasome inhibitor MG132. These results demonstrate the specific functional enhancements of the UPS that can provide neuroprotection in HD cells.
Intraneuronal protein aggregates of the mutated huntingtin in Huntington's disease (HD) brains suggest an overload and/or dysfunction of the ubiquitin-proteasome system (UPS). There is a general inhibition of the UPS in many brain regions (cerebellum, cortex, substantia nigra and caudate-putamen) and skin fibroblasts from HD patients. In the current experiment, the widely used mutant huntingtin-exon 1 CAG repeat HD transgenic mice model (R6/2) (with 144 CAG repeat and exon 1) during late-stage pathology, had increases in proteasome activity in the striatum. However, this discrepancy with HD patient tissue was not apparent in the mutant CAG repeat huntingtin full-length HD (YAC72) transgenic mouse model during post-symptomatic and late-stage pathology, which then also showed UPS inhibition similar to HD patients' brains. In both types of HD model mice, we determined biochemical changes, including expression of brain-derived neurotrophic factor (BDNF) and mitochondrial complex II/III (MCII/III) activities related to HD pathology. We found increases of both BDNF expression, and MCII/III activities in YAC72 transgenic mice, and no change of BDNF expression in R6/2 mice. Our data show that extreme CAG repeat lengths in R6/2 mice is paradoxically associated with increased proteasome activity, probably as a cellular compensatory biochemical change in response to the underlying mutation. Changes in HD patients for UPS function, BDNF expression and MCII/III activity are only partially modeled in R6/2 and YAC72 mice, with the latter at 16 months of age being most congruent with the human disease.
Huntington's disease (HD) is an autosomal neurodegenerative disease. Its manifestations is selective degeneration of medium-sized spiny neurons (MSN) in the striatum. The specificity of the vulnerability of these GABAergic MSNs can be explained by abnormal protein accumulation, excitotoxicity, mitochondrial dysfunction, and failure of trophic control, among other dysfunctions. In this study, we used in vitro and in vivo models of HD to study the effects of GABAergic neuron stimulation on the cellular protein degradation machinery. We administered the GABA(B) receptor agonist, baclofen, to wild-type or mutant huntingtin-expressing striatal cells (HD19 or HD43). Chymotrypsin-like proteasome activity and cell viability were significantly increased in the mutant huntingtin-expressing striatal cells (HD43) after GABA(B) receptor agonist treatment. In addition, we systemically administered baclofen to a HD model containing the entire human huntingtin gene with 128 CAG repeats (YAC128). Chymotrypsin-like proteasome activity was significantly increased in YAC128 transgenic mice after baclofen administration. Baclofen-injected mutant YAC128 mice also showed significantly reduced numbers of ubiquitin-positive neuronal intranuclear inclusions (NIIs) in the striatum. Baclofen markedly improved behavioral abnormalities in mutant YAC128 mice as determined by the rotarod performance test. These data indicate that stimulation of GABAergic neurons with the GABAB receptor agonist, baclofen, enhances ubiquitin-proteasome system (UPS) function and cell survival in in vitro and in vivo models of HD.
Introduction: Critically ill children in the pediatric intensive care unit (PICU) are at high risk for developing nutritional deficiencies and undernutrition is known to be a risk factor for morbidity and mortality. Malnutrition represents a continuous spectrum ranging from marginal nutrient status to severe metabolic and functional alterations and this in turn, affects clinical outcome. Objectives: The aim of the study was to assess nutritional status of critically ill children admitted to the PICU and its association to clinical outcomes. Methods: Critically ill children age 6 months to 18 years were prospectively enrolled on PICU admission. Nutritional status was assessed by weight for age (WFA: underweight), weight for height (WFH: wasting), height for age (HFA: stunting) z-scores and mid upper arm circumference (MUAC: wasting) according to the WHO. (1,2) Malnutrition was defined as mild, moderate, and severe if z-scores were > −1, > − 2, and > −3, respectively. Hospital and PICU length of stay (LOS), duration of mechanical ventilation (MV), and risk of mortality (ROM) by the Pediatric Index of Mortality 2 (PIM2) were obtained. Sensitivity and specificity of the MUAC to identify children with wasting (WFH) were calculated. Results: Two hundred and fifty children (136 males), aged 81 months (23-167; median (25-75 th IQR)), were prospectively included in the study. The hospital LOS was 8 (4-16) days; PICU LOS: 2 (1-4) days; duration of MV, 0 (0-1.5) days;
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