Under resting conditions, Pink1 knockout cells and cells derived from patients with PINK1 mutations display a loss of mitochondrial complex I reductive activity, causing a decrease in the mitochondrial membrane potential. Analyzing the phosphoproteome of complex I in liver and brain from Pink1(-/-) mice, we found specific loss of phosphorylation of serine-250 in complex I subunit NdufA10. Phosphorylation of serine-250 was needed for ubiquinone reduction by complex I. Phosphomimetic NdufA10 reversed Pink1 deficits in mouse knockout cells and rescued mitochondrial depolarization and synaptic transmission defects in pink(B9)-null mutant Drosophila. Complex I deficits and adenosine triphosphate synthesis were also rescued in cells derived from PINK1 patients. Thus, this evolutionary conserved pathway may contribute to the pathogenic cascade that eventually leads to Parkinson's disease in patients with PINK1 mutations.
Growing axons are guided to their targets by attractive and repulsive cues. In the developing spinal cord, Netrin-1 and Shh guide commissural axons towards the midline. However, the combined inhibition of their activity in commissural axon turning assays does not completely abrogate turning towards floor plate tissue, suggesting that additional guidance cues are present. Here, we show that the prototypic angiogenic factor VEGF is secreted by the floor plate and is a chemoattractant for commissural axons in vitro and in vivo. Inactivation of Vegf in the floor plate or of its receptor Flk1 in commissural neurons causes axon guidance defects, while Flk1-blockade inhibits turning of axons to VEGF in vitro. Similar to Shh and Netrin-1, VEGF-mediated commissural axon guidance requires the activity of Src family kinases. Our results identify VEGF and Flk1 as a novel ligand / receptor pair controlling commissural axon guidance.
Background: PINK1 mutations affect mitochondrial homeostasis and cause Parkinson disease. Results: PINK1 is phosphorylated on the outer mitochondrial membrane. We show here that phosphorylation of serines 228 and 402 increases the capacity of PINK1 to phosphorylate its substrates Parkin and Ubiquitin. Conclusion: PINK1 phosphorylation regulates its kinase activity. Significance: Understanding PINK1 regulation is pivotal to unravel its mitochondrial function.
Our findings indicate that the relevance of reversion for progression risk depends on the MCI subtype. Subtype specificity and longitudinal characterization are required for the reliable identification of individuals at high risk of developing dementia.
The exposure of surface dressing workers to polycyclic aromatic hydrocarbons (PAH) was studied. Four different paving sites, at which coal tar-containing binders were applied, were selected as work sites with high exposure levels of PAH. Breathing zone airborne particulates, contamination of the skin with PAH, and 1-hydroxypyrene in urine of the workers involved in chip sealing were determined. Substantial concentrations of cyclohexane-soluble airborne particulate matter were found (GM = 0.2 mg/m3, n = 28). Skin contamination was determined using two different methods: with exposure pads and by hand washing. Pads were mounted on several parts of the body: wrist, elbow, neck, shoulder, and ankle. The pads located on the wrist appeared to be the most contaminated (pyrene: GM = 22 ng/1.77 cm2, n = 40). The end-of-shift hand washing showed that the hands of the workers were contaminated with PAH (pyrene: GM = 70 micrograms, n = 35). Preshift hand washing showed far lower, but detectable, quantities of PAH on workers' hands (pyrene: GM = 5 micrograms, n = 35). Enhanced levels of urinary 1-hydroxypyrene among the workers were found. The highest levels were found in the end-of-shift urine samples. Correlations between the pyrene exposure variables were studied. Significant positive correlations were found between pyrene on the wrist pad versus end-of-shift urinary 1-hydroxypyrene; between pyrene on the hands versus end-of-shift urinary 1-hydroxypyrene; and between the two different skin contamination variables.
Introduction:Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.
Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives. Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes. Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.
Increasing recognition that apathy is one of the most prevalent behavioral and psychological symptoms of dementia and causes substantial caregiver distress has led to trials evaluating psychosocial and pharmacological treatments of apathy in dementia. We evaluated evidence of the efficacy of pharmacotherapies for apathy in dementia from studies since 2013. Previously reported benefits of acetylcholinesterase inhibitors and memantine were not replicated in recent studies. Antidepressants had mixed results with positive effects for apathy shown only for agomelatine, while stimulants, analgesics, and oxytocin study results were inconclusive. For some approaches, such as antipsychotic review, positive effects were found only in combination with nonpharmacological approaches. Relatively few studies assessed apathy outcomes specifically, complicating interpretation of potentially positive treatment effects; none dissected outcomes for emotional, motivational and behavioral components of apathy. Better trial design and more detailed analysis are needed in order to evaluate outcomes of pharmacological treatments for apathy.
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