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Progress in Neurobiology Dec 2023Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient...
Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson's Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of C. elegans resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from C. elegans to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.
Topics: Humans; Mice; Animals; Aged; Calcium; Reactive Oxygen Species; TRPM Cation Channels; Caenorhabditis elegans; Dopaminergic Neurons; Parkinson Disease; GTP Phosphohydrolases; Caenorhabditis elegans Proteins
PubMed: 37739206
DOI: 10.1016/j.pneurobio.2023.102530 -
Magnetic Resonance in Medical Sciences... Feb 2024Neuromelanin is visualized by optimizing the conditions of longitudinal relaxation (T1)-weighted imaging (T1WI). Although it was originally developed in 2D imaging, 3D...
PURPOSE
Neuromelanin is visualized by optimizing the conditions of longitudinal relaxation (T1)-weighted imaging (T1WI). Although it was originally developed in 2D imaging, 3D imaging has been also reported, and T1WI sequences with magnetization transfer (MT) pulses are now widely used in 3D gradient echo (GRE) sequences. In this study, we assert that the use of spectral presaturation with inversion recovery (SPIR) may also be useful as an alternative to MT pulses, and we optimize SPIR and compare it with MT.
METHODS
Neuromelanin images with MT pulse and SPIR (flip angles [FAs] = 19º, 22º, and 25º) were acquired from 30 healthy volunteers. To achieve the same acquisition time of 5 min, the slab thickness of the MT images was less than 1/3 of those of the SPIR images; the acquisition areas for MT and SPIR were the brainstem and the whole brain, respectively. Visual and quantitative evaluation was performed and compared on the four sequences acquired for the substantia nigra pars compacta (SNc) and the locus coeruleus (LC). For visual assessment, we used the mean score from a 3-point scale by two evaluators. For quantitative evaluation, the contrast ratios of SNc and LC were calculated in comparison with the background tissue signal.
RESULTS
In visual assessments, the mean scores of the SPIR FA19º and FA22º images were better than others in the SNc. Regarding LC, the SPIR FA22º image yielded the best mean score. In quantitative evaluations, the MT image was significantly lower than the other three images in SNc. Regarding LC, there were no significant differences among the four acquired images (MT and SPIR FA19º, FA22º, and FA25º).
CONCLUSIONS
Detection of neuromelanin in SNc and LC was improved by the use of SPIR compared to MT pulse in 3D neuromelanin imaging.
PubMed: 38382996
DOI: 10.2463/mrms.mp.2023-0095 -
Brain Research Bulletin Oct 2023Parkinson's disease (PD) is the second largest neurodegenerative disorder caused by the decreased number of dopaminergic (DAc) neurons in the substantia nigra pars...
Parkinson's disease (PD) is the second largest neurodegenerative disorder caused by the decreased number of dopaminergic (DAc) neurons in the substantia nigra pars compacta (SNpc). There is evidence that oxidative stress can contribute degeneration of DAc neurons in SNpc which is mainly caused by apoptotic cell death. Thus, suppressing oxidative stress and apoptosis of DAc neurons is an effective strategy to mitigate the progress of PD. Astaxanthin (AST) is a carotenoid, which mainly exists in marine organisms and is a powerful biological antioxidant. In this study, we aimed to determine the neuroprotective effect of AST on paraquat (PQ) -induced models of PD in vitro and in vivo. Here, we showed that AST significantly enhanced cell survival of SH-SY5Y cells against PQ toxicity by suppressing apoptotic cell death and oxidative stress. Moreover, we found that AST significantly ameliorated PQ-induced behavioral disorders associated with PD in C57BL/6 J mice and the damage to DAc neurons in the SNpc of mice. Lastly, we found that the neuroprotective effects of AST were conducted through inhibiting PQ-induced activation of MAPK signaling. In conclusion, our study indicates that AST had a strong protective effect on PQ-induced oxidative stress and antagonized apoptotic cell death in SH-SY5Y cells and PQ-induced mice PD model, which might provide new insights of AST for PD treatment.
Topics: Humans; Animals; Mice; Mice, Inbred C57BL; Parkinson Disease; Paraquat; Dopaminergic Neurons; Neuroblastoma; Disease Models, Animal
PubMed: 37708917
DOI: 10.1016/j.brainresbull.2023.110762 -
BioRxiv : the Preprint Server For... Nov 2023Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars...
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars compacta (SNc). Rit2 is a reported PD risk allele, and recent single cell transcriptomic studies identified a major RIT2 cluster in PD DA neurons, potentially linking Rit2 expression loss to a PD patient cohort. However, it is still unknown whether Rit2 loss itself is causative for PD or PD-like symptoms. Here we report that conditional Rit2 silencing in mouse DA neurons drove motor dysfunction that occurred earlier in males than females and was rescued at early stages by either inhibiting the DA transporter (DAT) or with L-DOPA treatment. Motor dysfunction was accompanied by decreased DA release, striatal DA content, phenotypic DAergic markers, DA neurons, and DAergic terminals, with increased pSer129-alpha synuclein and pSer935-LRRK2 expression. These results provide the first evidence that Rit2 loss is causal for SNc cell death and a PD-like phenotype, and reveal key sex-specific differences in the response to Rit2 loss.
PubMed: 37162843
DOI: 10.1101/2023.04.26.538430 -
BioRxiv : the Preprint Server For... Aug 2023Several midbrain nuclei degenerate in Parkinson's Disease (PD). Many of these nuclei share the common characteristics that are thought to contribute to their selective...
Several midbrain nuclei degenerate in Parkinson's Disease (PD). Many of these nuclei share the common characteristics that are thought to contribute to their selective vulnerability, including pacemaking activity and high levels of calcium influx. In addition to the well-characterized dopaminergic neurons of the substantia nigra pars compacta (SNc), the cholinergic neurons of the pedunculopontine nucleus (PPN) also degenerate in PD. It is well established that the low-threshold L-type calcium current is a main contributor to tonic calcium in SNc dopaminergic neurons and is hypothesized to contribute to their selective vulnerability. However, it is not yet clear whether the vulnerable PPN cholinergic neurons share this property. Therefore, we used two-photon dendritic calcium imaging and whole-cell electrophysiology to evaluate the role of L-type calcium channels in the tonic and phasic activity of PPN neurons and the corresponding dendritic calcium signal and directly compare these characteristics to SNc neurons. We found that blocking L-type channels reduces tonic firing rate and dendritic calcium levels in SNc neurons. By contrast, the calcium load in PPN neurons during pacemaking did not depend on L-type channels. However, we find that blocking L-type channels reduces phasic calcium influx in PPN dendrites. Together, these findings show that L-type calcium channels play different roles in the activity of SNc and PPN neurons, and suggest that low-threshold L-type channels are not responsible for tonic calcium levels in PPN cholinergic neurons and are therefore not likely to be a source of selective vulnerability in these cells.
PubMed: 37693427
DOI: 10.1101/2023.08.28.555184 -
MedRxiv : the Preprint Server For... Jul 2023Substantia nigra pars compacta (SNc) and locus coeruleus (LC) are neuromelanin-rich nuclei implicated in diverse cognitive and motor processes in normal brain function...
Substantia nigra pars compacta (SNc) and locus coeruleus (LC) are neuromelanin-rich nuclei implicated in diverse cognitive and motor processes in normal brain function and disease. However, their roles in aging and neurodegenerative disease mechanisms have remained unclear due to a lack of tools to study them . Preclinical and post-mortem human investigations indicate that the relationship between tissue neuromelanin content and neurodegeneration is complex. Neuromelanin exhibits both neuroprotective and cytotoxic characteristics, and tissue neuromelanin content varies across the lifespan, exhibiting an inverted U-shaped relationship with age. Neuromelanin-sensitive MRI (NM-MRI) is an emerging modality that allows measurement of neuromelanin-associated contrast in SNc and LC in humans. NM-MRI robustly detects disease effects in these structures in neurodegenerative and psychiatric conditions, including Parkinson's disease (PD). Previous NM-MRI studies of PD have largely focused on detecting disease group effects, but few studies have reported NM-MRI correlations with phenotype. Because neuromelanin dynamics are complex, we hypothesize that they are best interpreted in the context of both disease stage and aging, with neuromelanin loss correlating with symptoms most clearly in advanced stages where neuromelanin loss and neurodegeneration are coupled. We tested this hypothesis using NM-MRI to measure SNc and LC volumes in healthy older adult control individuals and in PD patients with and without freezing of gait (FOG), a severe and disabling PD symptom. We assessed for group differences and correlations between NM-MRI measures and aging, cognition and motor deficits. SNc volume was significantly decreased in PD with FOG compared to controls. SNc volume correlated significantly with motor symptoms and cognitive measures in PD with FOG, but not in PD without FOG. SNc volume correlated significantly with aging in PD. When PD patients were stratified by disease duration, SNc volume correlated with aging, cognition, and motor deficits only in PD with disease duration >5 years. We conclude that in severe or advanced PD, identified by either FOG or disease duration >5 years, the observed correlations between SNc volume and aging, cognition, and motor function may reflect the coupling of neuromelanin loss with neurodegeneration and the associated emergence of a linear relationship between NM-MRI measures and phenotype.
PubMed: 37461735
DOI: 10.1101/2023.07.04.23292227 -
Cureus Feb 2024Parkinson's disease (PD) is a complex neurological, degenerative clinical condition depicted by the advancing loss of dopaminergic neurons in the substantia nigra pars... (Review)
Review
Parkinson's disease (PD) is a complex neurological, degenerative clinical condition depicted by the advancing loss of dopaminergic neurons in the substantia nigra pars compacta, which manifests itself as a myriad of sensorimotor and non-motor signs in patients. The disease occurs due to the reduced levels of the neurotransmitter dopamine in the brain, which is primarily associated with functional characteristics regarding mobility and cognition. The basal ganglion is mainly involved in the generation of cognitive functions and therefore is the most significantly associated area in PD. Since the classical diagnosis and assessment of PD depends majorly on the appearance of motor characteristics, which only arise when ~60-80% of the dopamine neuronal cell death has already occurred, it is imperative we focus on identifying biomarkers that can help us assess and diagnose PD in the earlier stages of disease progression, thus providing a better prognosis for the patients. This review article will focus on the different biomarkers that are currently available and in use, divided under the headings of clinical, biological, imaging, and genetic biomarkers, and assess their specificity and sensitivity toward providing an early assessment of Parkinson's for the patients and the future of preclinical diagnostics using molecular biomarkers. PD affects over 1% of the population worldwide and only ranks second to Alzheimer's disease in the context of its incidence and consequent socioeconomic burden. While recent breakthroughs in biomarkers have dramatically improved patients' odds of survival and prognosis, it still remains primarily a symptomatic diagnostic tool. It is an area of research that requires to focus on creating more advanced approaches toward diagnosing PD early, involving clinical diagnostics, neuroimaging technology, and molecular biology collaborations to provide the highest degree of care and quality of life that a Parkinson's patient deserves.
PubMed: 38500934
DOI: 10.7759/cureus.54337 -
NPJ Parkinson's Disease Jan 2024Parkinson's disease (PD) is a prevalent neurodegenerative disorder that presents a diagnostic challenge due to symptom overlap with other disorders. Neuromelanin (NM)...
Parkinson's disease (PD) is a prevalent neurodegenerative disorder that presents a diagnostic challenge due to symptom overlap with other disorders. Neuromelanin (NM) imaging is a promising biomarker for PD, but adoption has been limited, in part due to subpar performance at standard MRI field strengths. We aimed to evaluate the diagnostic utility of ultra-high field 7T NM-sensitive imaging in the diagnosis of PD versus controls and essential tremor (ET), as well as NM differences among PD subtypes. A retrospective case-control study was conducted including PD patients, ET patients, and controls. 7T NM-sensitive 3D-GRE was acquired, and substantia nigra pars compacta (SNpc) volumes, contrast ratios, and asymmetry indices were calculated. Statistical analyses, including general linear models and ROC curves, were employed. Twenty-one PD patients, 13 ET patients, and 18 controls were assessed. PD patients exhibited significantly lower SNpc volumes compared to non-PD subjects. SNpc total volume showed 100% sensitivity and 96.8% specificity (AUC = 0.998) for differentiating PD from non-PD and 100% sensitivity and 95.2% specificity (AUC = 0.996) in differentiating PD from ET. Contrast ratio was not significantly different between PD and non-PD groups (p = 0.07). There was also significantly higher asymmetry index in SNpc volume in PD compared to non-PD cohorts (p < 0.001). NM signal loss in PD predominantly involved the inferior, posterior, and lateral aspects of SNpc. Akinetic-rigid subtype showed more significant NM signal loss compared to tremor dominant subtype (p < 0.001). 7T NM imaging demonstrates potential as a diagnostic tool for PD, including potential distinction between subtypes, allowing improved understanding of disease progression and subtype-related characteristics.
PubMed: 38191546
DOI: 10.1038/s41531-024-00631-3 -
International Journal of Molecular... Apr 2024Parkinson's disease (PD) is the second most common neurodegenerative disorder. Dopamine (DA) neurons in the substantia nigra pars compacta, which have axonal projections...
Parkinson's disease (PD) is the second most common neurodegenerative disorder. Dopamine (DA) neurons in the substantia nigra pars compacta, which have axonal projections to the dorsal striatum (dSTR), degenerate in PD. In contrast, DA neurons in the ventral tegmental area, with axonal projections to the ventral striatum, including the nucleus accumbens (NAcc) shell, are largely spared. This study aims to uncover the relative contributions of glycolysis and oxidative phosphorylation (OxPhos) to DA release in the striatum. We measured evoked DA release in mouse striatal brain slices using fast-scan cyclic voltammetry applied every two minutes. Blocking OxPhos resulted in a greater reduction in evoked DA release in the dSTR when compared to the NAcc shell, while blocking glycolysis caused a more significant decrease in evoked DA release in the NAcc shell than in the dSTR. Furthermore, when glycolysis was bypassed in favor of direct OxPhos, evoked DA release in the NAcc shell decreased by approximately 50% over 40 min, whereas evoked DA release in the dSTR was largely unaffected. These results demonstrate that the dSTR relies primarily on OxPhos for energy production to maintain evoked DA release, whereas the NAcc shell depends more on glycolysis. Consistently, two-photon imaging revealed higher oxidation levels of DA terminals in the dSTR than in the NAcc shell. Together, these findings partly explain the selective vulnerability of DA terminals in the dSTR to degeneration in PD.
Topics: Animals; Dopamine; Mice; Glycolysis; Oxidative Phosphorylation; Corpus Striatum; Male; Mice, Inbred C57BL; Dopaminergic Neurons; Nucleus Accumbens
PubMed: 38731799
DOI: 10.3390/ijms25094580 -
Frontiers in Bioengineering and... 2023Targeted gene editing is proposed as a therapeutic approach for numerous disorders, including neurological diseases. As the brain is organized into neural networks, it...
Targeted gene editing is proposed as a therapeutic approach for numerous disorders, including neurological diseases. As the brain is organized into neural networks, it is critical to understand how anatomically connected structures are affected by genome editing. For example, neurons in the substantia nigra pars compacta (SNpc) project to the striatum, and the striatum contains neurons that project to the substantia nigra pars reticulata (SNpr). Here, we report the effect of injecting genome editors into the striatum of Ai14 reporter mice, which have a LoxP-flanked stop cassette that prevents expression of the red fluorescent protein tdTomato. Two weeks following intracerebral delivery of either synthetic nanocapsules (NCs) containing CRISPR ribonucleoprotein targeting the tdTomato stop cassette or adeno-associated virus (AAV) vectors expressing Cre recombinase, the brains were collected, and the presence of tdTomato was assessed in both the striatum and SN. TdTomato expression was observed at the injection site in both the NC- and AAV-treated groups and typically colocalized with the neuronal marker NeuN. In the SN, tdTomato-positive fibers were present in the pars reticulata, and SNpr area expressing tdTomato correlated with the size of the striatal genome edited area. These results demonstrate anterograde axonal transport of reporter gene protein products to the SNpr following neuronal genome editing in the striatum.
PubMed: 37564994
DOI: 10.3389/fbioe.2023.1237613