| 1. |
- Deshpande, Prasannakumar, et al.
(författare)
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Protein synthesis is suppressed in sporadic and familial Parkinson’s disease by LRRK2
- 2020
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Ingår i: FASEB Journal. - 0892-6638. ; 34:11, s. 14217-14233
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Tidskriftsartikel (refereegranskat)abstract
- Gain of function LRRK2-G2019S is the most frequent mutation found in familial and sporadic Parkinson's disease. It is expected therefore that understanding the cellular function of LRRK2 will provide insight on the pathological mechanism not only of inherited Parkinson's, but also of sporadic Parkinson's, the more common form. Here, we show that constitutive LRRK2 activity controls nascent protein synthesis in rodent neurons. Specifically, pharmacological inhibition of LRRK2, Lrrk2 knockdown or Lrrk2 knockout, all lead to increased translation. In the rotenone model for sporadic Parkinson's, LRRK2 activity increases, dopaminergic neuron translation decreases, and the neurites atrophy. All are prevented by LRRK2 inhibitors. Moreover, in striatum and substantia nigra of rotenone treated rats, phosphorylation changes are observed on eIF2α-S52(↑), eIF2s2-S2(↓), and eEF2-T57(↑) in directions that signify protein synthesis arrest. Significantly, translation is reduced by 40% in fibroblasts from Parkinson's patients (G2019S and sporadic cases alike) and this is reversed upon LRRK2 inhibitor treatment. In cells from multiple system atrophy patients, translation is unchanged suggesting that repression of translation is specific to Parkinson's disease. These findings indicate that repression of translation is a proximal function of LRRK2 in Parkinson's pathology.
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| 2. |
- Johansson, Jarkko, et al.
(författare)
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Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects
- 2019
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group. - 0893-133X .- 1740-634X. ; 44:9, s. 1667-1673
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Tidskriftsartikel (refereegranskat)abstract
- Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and [11C]carfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60 min and at 300–360 min post naloxone. Naloxone plasma concentrations peaked at ~20 min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at ~10 min). Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN doses, respectively. The estimated half-life of occupancy disappearance was ~100 min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.
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| 3. |
- Tuominen, Jarno, et al.
(författare)
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Segregated brain state during hypnosis
- 2021
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Ingår i: Neuroscience of Consciousness. - : Oxford University Press. - 2057-2107. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Can the brain be shifted into a different state using a simple social cue, as tests on highly hypnotizable subjects would suggest? Demonstrating an altered global brain state is difficult. Brain activation varies greatly during wakefulness and can be voluntarily influenced. We measured the complexity of electrophysiological response to transcranial magnetic stimulation in one 'hypnotic virtuoso'. Such a measure produces a response arguably outside the subject's voluntary control and has been proven adequate for discriminating conscious from unconscious brain states. We show that a single-word hypnotic induction robustly shifted global neural connectivity into a state where activity remained sustained but failed to ignite strong, coherent activity in frontoparietal cortices. Changes in perturbational complexity indicate a similar move towards a more segregated state. We interpret these findings to suggest a shift in the underlying state of the brain, likely moderating subsequent hypnotic responding.
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