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NeuroImage. Clinical 2024Several genetic pathogenic variants increase the risk of Parkinson's disease (PD) with pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene being among...
Multi-tracer PET correlation analysis reveals disease-specific patterns in Parkinson's disease and asymptomatic LRRK2 pathogenic variant carriers compared to healthy controls.
Several genetic pathogenic variants increase the risk of Parkinson's disease (PD) with pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene being among the most common. A joint pattern analysis based on multi-set canonical correlation analysis (MCCA) was utilized to extract PD and LRRK2 pathogenic variant-specific spatial patterns in relation to healthy controls (HCs) from multi-tracer Positron Emission Tomography (PET) data. Spatial patterns were extracted for individual subject cohorts, as well as for pooled subject cohorts, to explore whether complementary spatial patterns of dopaminergic denervation are different in the asymptomatic and symptomatic stages of PD. The MCCA results are also compared to the traditional univariate analysis, which serves as a reference. We identified PD-induced spatial distribution alterations common to DAT and VMAT2 in both asymptomatic LRRK2 pathogenic variant carriers and PD subjects. The inclusion of HCs in the analysis demonstrated that the dominant common PD-induced pattern is related to an overall dopaminergic terminal density denervation, followed by asymmetry and rostro-caudal gradient with deficits in the less affected side still being the best marker of disease progression. The analysis was able to capture a trend towards PD-related patterns in the LRRK2 pathogenic variant carrier cohort with increasing age in line with the known increased risk of this patient cohort to develop PD as they age. The advantage of this method thus resides in its ability to identify not only regional differences in tracer binding between groups, but also common disease-related alterations in the spatial distribution patterns of tracer binding, thus potentially capturing more complex aspects of disease induced alterations.
Topics: Humans; Parkinson Disease; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Positron-Emission Tomography; Middle Aged; Female; Male; Aged; Adult; Heterozygote; Brain; Vesicular Monoamine Transport Proteins; Dopamine Plasma Membrane Transport Proteins
PubMed: 38599001
DOI: 10.1016/j.nicl.2024.103600 -
Human Brain Mapping Apr 2024Isolated REM sleep behavior disorder (iRBD) is an early stage of synucleinopathy with most patients progressing to Parkinson's disease (PD) or related conditions....
Isolated REM sleep behavior disorder (iRBD) is an early stage of synucleinopathy with most patients progressing to Parkinson's disease (PD) or related conditions. Quantitative susceptibility mapping (QSM) in PD has identified pathological iron accumulation in the substantia nigra (SN) and variably also in basal ganglia and cortex. Analyzing whole-brain QSM across iRBD, PD, and healthy controls (HC) may help to ascertain the extent of neurodegeneration in prodromal synucleinopathy. 70 de novo PD patients, 70 iRBD patients, and 60 HCs underwent 3 T MRI. T1 and susceptibility-weighted images were acquired and processed to space standardized QSM. Voxel-based analyses of grey matter magnetic susceptibility differences comparing all groups were performed on the whole brain and upper brainstem levels with the statistical threshold set at family-wise error-corrected p-values <.05. Whole-brain analysis showed increased susceptibility in the bilateral fronto-parietal cortex of iRBD patients compared to both PD and HC. This was not associated with cortical thinning according to the cortical thickness analysis. Compared to iRBD, PD patients had increased susceptibility in the left amygdala and hippocampal region. Upper brainstem analysis revealed increased susceptibility within the bilateral SN for both PD and iRBD compared to HC; changes were located predominantly in nigrosome 1 in the former and nigrosome 2 in the latter group. In the iRBD group, abnormal dopamine transporter SPECT was associated with increased susceptibility in nigrosome 1. iRBD patients display greater fronto-parietal cortex involvement than incidental early-stage PD cohort indicating more widespread subclinical neuropathology. Dopaminergic degeneration in the substantia nigra is paralleled by susceptibility increase, mainly in nigrosome 1.
Topics: Humans; REM Sleep Behavior Disorder; Synucleinopathies; Brain; Substantia Nigra; Parkinson Disease; Iron
PubMed: 38590155
DOI: 10.1002/hbm.26675 -
Acta Neurobiologiae Experimentalis Mar 2024Morphine changes neurotransmitter release, including norepinephrine, dopamine, and serotonin. Decynium‑22 (D22) inhibits an alternative neurotransmitter removal...
Morphine changes neurotransmitter release, including norepinephrine, dopamine, and serotonin. Decynium‑22 (D22) inhibits an alternative neurotransmitter removal pathway, namely uptake‑2. Uptake‑2 includes plasma membrane monoamine transporter (PMAT) and organic cation transporters that have a low affinity, but high capacity for uptake of various monoamines such as norepinephrine, dopamine, and serotonin. This study was done to assess the effect of uptake‑2 inhibition on morphine‑induced conditioned place preference (CPP) and analgesia. In this study, the effects of morphine and/or D22 on CPP were evaluated following intraperitoneal injection in mice. Afterward, changes in motor activity were evaluated by the open field test. Using the tail‑flick model, the effects of D22 and/or morphine were evaluated on the pain threshold. The results showed that 20 mg/kg of morphine induced a place preference response. D22, at the dose of 0.03 mg/kg, caused place avoidance, while at the dose of 0.3 mg/kg, it produced a notable place preference response. Co‑administration of D22 and morphine showed that morphine reversed the CPP aversion induced by D22 at the lowest dose. Motor activity did not alter. In the tail‑flick test, morphine, at the dose of 3 mg/kg but not 1 mg/kg, increased the pain threshold. D22 induced significant analgesic responses. Co‑administration of D22 and morphine caused considerable analgesic effects. The findings revealed that D22 induced both conditioned aversion and preference depending on the dose while morphine induced CPP. Both drugs produced analgesia.
Topics: Mice; Animals; Morphine; Dopamine; Serotonin; Pain; Analgesics; Norepinephrine; Neurotransmitter Agents; Dose-Response Relationship, Drug
PubMed: 38587327
DOI: 10.55782/ane-2024-2517 -
Translational Neurodegeneration Apr 2024
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Multiple System Atrophy; Brain; Positron-Emission Tomography
PubMed: 38566170
DOI: 10.1186/s40035-024-00411-2 -
Research Square Mar 2024Missense mutations of PARK20/ (synaptojanin1/Synj1) have been linked to complex forms of familial parkinsonism, however, the molecular and cellular changes associated...
Missense mutations of PARK20/ (synaptojanin1/Synj1) have been linked to complex forms of familial parkinsonism, however, the molecular and cellular changes associated with dopaminergic dysfunction remains unknown. We now report fast depletion of evoked dopamine (DA) and altered maintenance of the axonal dopamine transporter (DAT) in the neurons. While Synj1 has been traditionally known to facilitate the endocytosis of synaptic vesicles, we demonstrated that axons of cultured neurons exhibit an increase of total DAT but a reduction of the surface DAT, which could be exacerbated by neuronal activity. We revealed that the loss of surface DAT is specifically associated with the impaired 5'-phosphatase activity of Synj1 and the hyperactive downstream PI(4,5)P-PKCβ pathway. Thus, our findings provided important mechanistic insight for Synj1-regulated DAT trafficking integral to dysfunctional DA signaling in early parkinsonism.
PubMed: 38559229
DOI: 10.21203/rs.3.rs-4021466/v1 -
BioRxiv : the Preprint Server For... Mar 2024Alcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the...
Alcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. Here, 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods. After the last abstinence period, we paired direct sub-second dopamine monitoring via voltammetry in nucleus accumbens slices with RNA-sequencing of the ventral tegmental area. We found persistent augmentation of dopamine transporter function, kappa opioid receptor sensitivity, and dynorphin release - all inhibitory regulators which act to decrease extracellular dopamine. Surprisingly, though transcript expression was not altered, the relationship between gene expression and functional readouts of these encoded proteins was highly dynamic and altered by drinking history. These results outline the long-lasting synaptic impact of alcohol use and suggest that assessment of transcript-function relationships is critical for the rational design of precision therapeutics.
PubMed: 38559169
DOI: 10.1101/2024.03.15.584711 -
BioRxiv : the Preprint Server For... Mar 2024The dopamine transporter (DAT) plays a critical role in the central nervous system and has been implicated in numerous psychiatric disorders. The ligand-based approaches...
The dopamine transporter (DAT) plays a critical role in the central nervous system and has been implicated in numerous psychiatric disorders. The ligand-based approaches are instrumental to decipher the structure-activity relationship (SAR) of DAT ligands, especially the quantitative SAR (QSAR) modeling. By gathering and analyzing data from literature and databases, we systematically assemble a diverse range of ligands binding to DAT, aiming to discern the general features of DAT ligands and uncover the chemical space for potential novel DAT ligand scaffolds. The aggregation of DAT pharmacological activity data, particularly from databases like ChEMBL, provides a foundation for constructing robust QSAR models. The compilation and meticulous filtering of these data, establishing high-quality training datasets with specific divisions of pharmacological assays and data types, along with the application of QSAR modeling, prove to be a promising strategy for navigating the pertinent chemical space. Through a systematic comparison of DAT QSAR models using training datasets from various ChEMBL releases, we underscore the positive impact of enhanced data set quality and increased data set size on the predictive power of DAT QSAR models.
PubMed: 38558976
DOI: 10.1101/2024.03.06.583803 -
Biomedicines Mar 2024Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that...
Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that activates the hippocampal CA1 area in humans and is vital for memory reformulation and reconsolidation, is also impaired in patients with hippocampal lesions. In this work, we investigated the response to mismatch novelty, as occurs with the new location of known objects in a familiar environment, in the Li-pilocarpine rat model of TLE and its correlation with hippocampal monoaminergic markers. Animals showing spontaneous recurrent seizures () for at least 4 weeks at the time of behavioural testing showed impaired spatial learning in the radial arm maze, as described. Concurrently, rats displayed impaired exploratory responses to mismatch novelty, yet novel object recognition was not significantly affected in rats. While the levels of serotonin and dopamine transporters were mildly decreased in hippocampal membranes from rats, the levels on the norepinephrine transporter, tyrosine hydroxylase and dopamine-β-hydroxylase were enhanced, hinting for an augmentation, rather than an impairment in noradrenergic function in animals. Altogether, this reveals that mismatch novelty detection is particularly affected by hippocampal damage associated to the Li-pilocarpine model of epilepsy 4-8 weeks after the onset of and suggests that deficits in mismatch novelty detection may substantially contribute to cognitive impairment in MTLE. As such, behavioural tasks based on these aspects of mismatch novelty may prove useful in the development of cognitive therapy strategies aiming to rescue cognitive deficits observed in epilepsy.
PubMed: 38540244
DOI: 10.3390/biomedicines12030631 -
Brain Sciences Mar 2024Structural modifications to synthetic psychoactive cathinones (SPCs), a class of drugs that contain a β-keto modification of the phenethylamine pharmacophore of...
Structural modifications to synthetic psychoactive cathinones (SPCs), a class of drugs that contain a β-keto modification of the phenethylamine pharmacophore of amphetamine, induce differences in dopamine transporter (DAT) activity. Here, in vivo retrodialysis was utilized to deliver the SPCs 3,4-methylenedioxypyrovalerone (MDPV, a DAT inhibitor) or methylone (a DAT substrate) into the caudate putamen of male Sprague-Dawley rats. Dialysate samples were collected prior to and post drug administration, and temporal changes in dopamine concentration were quantified using HPLC-EC methods. Methylone elicited a 200% increase and MDPV a 470% increase in dopamine levels at the 10 min time point. The findings demonstrate that in vivo retrodialysis can be used to evaluate the effects of SPCs on neurotransmission in the brain.
PubMed: 38539653
DOI: 10.3390/brainsci14030265 -
PloS One 2024Monoamine transporters including transporters for serotonin, dopamine, and norepinephrine play key roles in monoaminergic synaptic signaling, involving in the molecular...
Structural bioinformatics studies of serotonin, dopamine and norepinephrine transporters and their AlphaFold2 predicted water-soluble QTY variants and uncovering the natural mutations of L->Q, I->T, F->Y and Q->L, T->I and Y->F.
Monoamine transporters including transporters for serotonin, dopamine, and norepinephrine play key roles in monoaminergic synaptic signaling, involving in the molecular etiology of a wide range of neurological and physiological disorders. Despite being crucial drug targets, the study of transmembrane proteins remains challenging due to their localization within the cell membrane. To address this, we present the structural bioinformatics studies of 7 monoamine transporters and their water-soluble variants designed using the QTY code, by systematically replacing the hydrophobic amino acids leucine (L), valine (V), isoleucine (I) and phenylalanine (F) with hydrophilic amino acids (glutamine (Q), threonine (T) and tyrosine (Y). The resulting QTY variants, despite significant protein transmembrane sequence differences (44.27%-51.85%), showed similar isoelectric points (pI) and molecular weights. While their hydrophobic surfaces significantly reduced, this change resulted in a minimal structural alteration. Quantitatively, Alphafold2 predicted QTY variant structures displayed remarkable similarity with RMSD 0.492Å-1.619Å. Accompanied by the structural similarities of substituted amino acids in the context of 1.5Å electron density maps, our study revealed multiple QTY and reverse QTY variations in genomic databases. We further analyzed their phenotypical and topological characteristics. By extending evolutionary game theory to the molecular foundations of biology, we provided insights into the evolutionary dynamics of chemically distinct alpha-helices, their usage in different chemotherapeutic applications, and open possibilities of diagnostic medicine. Our study rationalizes that QTY variants of monoamine transporters may not only become distinct tools for medical, structural, and evolutionary research, but these transporters may also emerge as contemporary therapeutic targets, providing a new approach to treatment for several conditions.
Topics: Dopamine; Serotonin; Water; Membrane Transport Proteins; Amino Acids; Norepinephrine; Computational Biology; Mutation; Dopamine Plasma Membrane Transport Proteins
PubMed: 38517879
DOI: 10.1371/journal.pone.0300340