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- Markaki, I., et al.
(författare)
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Cerebrospinal Fluid Levels of Kininogen-1 Indicate Early Cognitive Impairment in Parkinson’s Disease
- 2020
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Ingår i: Movement Disorders. - : John Wiley & Sons. - 0885-3185 .- 1531-8257.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cognitive impairment is common in patients with PD. Core markers of Alzheimer’s dementia have been related also to PD dementia, but no disease-specific signature to predict PD dementia exists to date. Objectives: The aim of this study was to investigate CSF markers associated with cognition in early PD. Methods: A high-throughput suspension bead array examined 216 proteins in CSF of 74 PD patients in the AETIONOMY project. Cognitive function was assessed with Repeatable Battery for the Assessment of the Neuropsychological Status, Montreal Cognitive Assessment, and Mini-Mental State Examination. Results: Of 69 patients with complete data, 34 had high (≥90) and 35 had low Repeatable Battery for the Assessment of the Neuropsychological Status total score (<90). Of 14 proteins in CSF that differed in levels between groups, increased kininogen-1, validated with several antibodies, was independently associated with lower Repeatable Battery for the Assessment of the Neuropsychological Status and Montreal Cognitive Assessment scores after adjustment for confounders. Conclusions: Kininogen-1 levels in CSF may serve as a marker of cognitive impairment in PD.
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| 12. |
- Kojima, R, et al.
(författare)
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Prosaposin Reduces α-Synuclein in Cells and Saposin C Dislodges it from Glucosylceramide-enriched Lipid Membranes
- 2022
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Ingår i: Journal of molecular neuroscience : MN. - : Springer Science and Business Media LLC. - 1559-1166 .- 0895-8696. ; 72:11, s. 2313-2325
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder affecting over 1% of the 65 + age population. Saposin C, a lysosomal protein required for the normal activity of glucocerebrosidase (GCase), may serve as a disease modifier in PD. Saposin C is cleaved from its precursor, Prosaposin (PSAP), which is secreted as an uncleaved protein and exerts neuroprotective effects. In this study, we aim to elucidate the neuroprotective roles of PSAP and saposin C in PD by evaluating their effects on α-synuclein accumulation in human neuroblastoma cells. Stable overexpression of PSAP reduced monomeric α-synuclein levels in SH-SY5Y cells, while PSAP knockdown by small interfering RNA led to the opposite effect, and those effects were independent of GCase activity. Autophagy flux was decreased by stable PSAP overexpression. Furthermore, a flow-through assay revealed that recombinant saposin C was able to detach α-synuclein from artificial glucosylceramide-enriched lipid membranes at the lysosomal pH. Taken together, our findings provide further evidence that PSAP and saposin C as key proteins involved in α-synuclein clearance by dislodging it from lipid membranes.
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- Lazarevic, V, et al.
(författare)
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α-Synuclein induced cholesterol lowering increases tonic and reduces depolarization-evoked synaptic vesicle recycling and glutamate release
- 2022
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Ingår i: NPJ Parkinson's disease. - : Springer Science and Business Media LLC. - 2373-8057. ; 8:1, s. 71-
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Tidskriftsartikel (refereegranskat)abstract
- α-Synuclein (α-syn) is a key molecule linked to Parkinson’s disease pathology. Physiologically, the monomeric α-syn in the presynaptic termini is involved in regulation of neurotransmission, but the pathophysiology of extracellular monomeric α-syn is still unknown. Utilizing both in vivo and in vitro approaches, we investigated how extracellular α-syn impact presynaptic structure and function. Our data revealed that treatment with exogenous α-syn leads to increased tonic and decreased depolarization-evoked synaptic vesicle (SV) recycling and glutamate release. This was associated with mobilization of molecularly distinct SV pools and reorganization of active zone components. Our study also showed that exogenous α-syn impaired neuronal cholesterol level and that the cholesterol binding domain of α-syn was sufficient to exert the same presynaptic phenotype as the full-length protein. The present study sheds new light on physiological functions of extracellular α-syn in overall maintenance of presynaptic activity that involves the reorganization of both presynaptic compartment and cholesterol-rich plasma membrane domains.
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- Sousa, VC, et al.
(författare)
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P11 deficiency increases stress reactivity along with HPA axis and autonomic hyperresponsiveness
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:7, s. 3253-3265
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Tidskriftsartikel (refereegranskat)abstract
- Patients suffering from mood disorders and anxiety commonly exhibit hypothalamic–pituitary–adrenocortical (HPA) axis and autonomic hyperresponsiveness. A wealth of data using preclinical animal models and human patient samples indicate that p11 deficiency is implicated in depression-like phenotypes. In the present study, we used p11-deficient (p11KO) mice to study potential roles of p11 in stress responsiveness. We measured stress response using behavioral, endocrine, and physiological readouts across early postnatal and adult life. Our data show that p11KO pups respond more strongly to maternal separation than wild-type pups, even though their mothers show no deficits in maternal behavior. Adult p11KO mice display hyperactivity of the HPA axis, which is paralleled by depression- and anxiety-like behaviors. p11 was found to be highly enriched in vasopressinergic cells of the paraventricular nucleus and regulates HPA hyperactivity in a V1B receptor-dependent manner. Moreover, p11KO mice display sympathetic–adrenal–medullary (SAM) axis hyperactivity, with elevated adrenal norepinephrine and epinephrine levels. Using conditional p11KO mice, we demonstrate that this SAM hyperactivity is partially regulated by the loss of p11 in serotonergic neurons of the raphe nuclei. Telemetric electrocardiogram measurements show delayed heart rate recovery in p11KO mice in response to novelty exposure and during expression of fear following auditory trace fear conditioning. Furthermore, p11KO mice have elevated basal heart rate in fear conditioning tests indicating increased autonomic responsiveness. This set of experiments provide strong and versatile evidence that p11 deficiency leads to HPA and SAM axes hyperresponsiveness along with increased stress reactivity.
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- Veenit, V, et al.
(författare)
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Impaired Aversive Memory Formation in GPR37L1KO Mice
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:22
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Tidskriftsartikel (refereegranskat)abstract
- GPR37L1 is an orphan G-protein-coupled receptor, which is implicated in neurological disorders, but its normal physiological role is poorly understood. Its close homologue, GPR37, is implicated in Parkinson’s disease and affective disorders. In this study, we set out to characterize adult and middle-aged global GPR37L1 knock-out (KO) mice regarding emotional behaviors. Our results showed that GPR37L1KO animals, except adult GPR37L1KO males, exhibited impaired retention of aversive memory formation as assessed by the shorter retention latency in a passive avoidance task. Interestingly, the viral-mediated deletion of GPR37L1 in conditional knockout mice in the hippocampus of middle-aged mice also showed impaired retention in passive avoidance tasks, similar to what was observed in global GPR37L1KO mice, suggesting that hippocampal GPR37L1 is involved in aversive learning processes. We also observed that middle-aged GPR37L1KO male and female mice exhibited a higher body weight than their wild-type counterparts. Adult and middle-aged GPR37L1KO female mice exhibited a reduced level of serum corticosterone and middle-aged GPR37L1KO females showed a reduced level of epinephrine in the dorsal hippocampus in the aftermath of passive avoidance task, with no such effects observed in GPR37L1KO male mice, suggesting that lack of GPR37L1 influences behavior and biochemical readouts in age- and sex-specific manners.
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