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Behavioural Brain Research Jun 2024Parkinson's is the most common neurodegenerative disease after Alzheimer's. Motor findings in Parkinson's occur as a result of the degeneration of dopaminergic neurons... (Review)
Review
Parkinson's is the most common neurodegenerative disease after Alzheimer's. Motor findings in Parkinson's occur as a result of the degeneration of dopaminergic neurons starting in the substantia nigra pars compacta and ending in the putamen and caudate nucleus. Loss of neurons and the formation of inclusions called Lewy bodies in existing neurons are characteristic histopathological findings of Parkinson's. The disease primarily impairs the functional capacity of the person with cardinal findings such as tremor, bradykinesia, etc., as a result of the loss of dopaminergic neurons in the substantia nigra. Experimental animal models of Parkinson's have been used extensively in recent years to investigate the pathology of this disease. These models are generally based on systemic or local(intracerebral) administration of neurotoxins, which can replicate many features of Parkinson's mammals. The development of transgenic models in recent years has allowed us to learn more about the modeling of Parkinson's. Applying animal modeling, which shows the most human-like effects in studies, is extremely important. It has been demonstrated that oxidative stress increases in many neurodegenerative diseases such as Parkinson's and various age-related degenerative diseases in humans and that neurons are sensitive to it. In cases where oxidative stress increases and antioxidant systems are inadequate, natural molecules such as flavonoids and polyphenols can be used as a new antioxidant treatment to reduce neuronal reactive oxygen species and improve the neurodegenerative process. Therefore, in this article, we examined experimental animal modeling in Parkinson's disease and the effect of green chemistry approaches on Parkinson's disease.
PubMed: 38844056
DOI: 10.1016/j.bbr.2024.115092 -
Frontiers in Cell and Developmental... 2023Neurons derived from human pluripotent stem cells (hPSCs) provide a valuable tool for studying human neural development and neurodegenerative diseases. The investigation... (Review)
Review
Neurons derived from human pluripotent stem cells (hPSCs) provide a valuable tool for studying human neural development and neurodegenerative diseases. The investigation of hPSC-based cell therapy, involving the differentiation of hPSCs into target cells and their transplantation into affected regions, is of particular interest. One neurodegenerative disease that is being extensively studied for hPSC-based cell therapy is Parkinson's disease (PD), the second most common among humans. Various research groups are focused on differentiating hPSCs into ventral midbrain dopaminergic (vmDA) progenitors, which have the potential to further differentiate into neurons closely resembling DA neurons found in the substantia nigra pars compacta (SNpc) after transplantation, providing a promising treatment option for PD. In experiments, where hPSC-derived vmDA progenitor cells were transplanted into the striatum or SNpc of animal PD models, the transplanted cells demonstrated stable engraftment and resulted in behavioral recovery in the transplanted animals. Several differentiation protocols have been developed for this specific cell therapy. However, the lack of a reliable live-cell lineage identification method presents a significant obstacle in confirming the precise lineage of the differentiated cells intended for transplantation, as well as identifying potential contamination by non-vmDA progenitors. This deficiency increases the risk of adverse effects such as dyskinesias and tumorigenicity, highlighting the importance of addressing this issue before proceeding with transplantation. Ensuring the differentiation of hPSCs into the target cell lineage is a crucial step to guarantee precise therapeutic effects in cell therapy. To underscore the significance of lineage identification, this review focuses on the differentiation protocols of hPSC-derived vmDA progenitors developed by various research groups for PD treatment. Moreover, experimental results following transplantation were carefully analyzed. The encouraging outcomes from these experiments demonstrate the potential efficacy and safety of hPSC-derived vmDA progenitors for PD cell therapy. Additionally, the results of clinical trials involving the use of hPSC-derived vmDA progenitors for PD treatment were briefly reviewed, shedding light on the progress and challenges faced in translating this promising therapy into clinical practice.
PubMed: 37886394
DOI: 10.3389/fcell.2023.1288168 -
Aging Cell Oct 2023Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in the brain. These LBs are primarily composed of α-Synuclein (α-Syn), which has...
Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in the brain. These LBs are primarily composed of α-Synuclein (α-Syn), which has aggregated. A recent report proposes that CCAAT/enhancer-binding proteins β (C/EBPβ) may act as an age-dependent transcription factor for α-Syn, thereby initiating PD pathologies by regulating its transcription. Potential therapeutic approaches to address PD could involve targeting the regulation of α-Syn by C/EBPβ. This study has revealed that Nrf2, also known as nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), suppresses the transcription of C/EBPβ in SH-SY5Y cells when treated with MPP . To activate Nrf2, sulforaphane, an Nrf2 activator, was administered. Additionally, C/EBPβ was silenced using C/EBPβ-DNA/RNA heteroduplex oligonucleotide (HDO). Both approaches successfully reduced abnormal α-Syn expression in primary neurons treated with MPP . Furthermore, sustained activation of Nrf2 via its activator or inhibition of C/EBPβ using C/EBPβ-HDO resulted in a reduction of aberrant α-Syn expression, thus leading to an improvement in the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) in mouse models induced by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and those treated with preformed fibrils (PFFs). The data presented in this study illustrate that the activation of Nrf2 may provide a potential therapeutic strategy for PD by inhibiting the abnormal C/EBPβ/α-Syn signaling pathway.
Topics: Animals; Humans; Mice; Dopaminergic Neurons; Neuroblastoma; NF-E2-Related Factor 2; Parkinson Disease; Signal Transduction; alpha-Synuclein; CCAAT-Enhancer-Binding Proteins
PubMed: 37614147
DOI: 10.1111/acel.13958 -
Parkinsonism & Related Disorders Feb 2024The four features of Parkinson's disease (PD), which also manifests other non-motor symptoms, are bradykinesia, tremor, postural instability, and stiffness. The... (Review)
Review
The four features of Parkinson's disease (PD), which also manifests other non-motor symptoms, are bradykinesia, tremor, postural instability, and stiffness. The pathogenic causes of Parkinsonism include Lewy bodies, intracellular protein clumps of αsynuclein, and the degeneration of dopaminergic neurons in the substantia nigra's pars compacta region. The pathophysiology of PD is still poorly understood due to the complexity of the illness. The apoptotic cell death of neurons in PD, however, has been linked to a variety of intracellular mechanisms, according to a wide spectrum of study. The endoplasmic reticulum's stress, decreased levels of neurotrophic factors, oxidative stress, mitochondrial dysfunction, catabolic alterations in dopamine, and decreased activity of tyrosine hydroxylase are some of these causes. The herbicide paraquat has been used in laboratory studies to create a variety of PD pathological features in numerous in-vitro and in-vivo animals. Due to the unique neurotoxicity that paraquat causes, understanding of the pathophysiology of PD has changed. Parkinson's disease (PD) is more likely to develop among people exposed to paraquat over an extended period of time, according to epidemiological studies. Thanks to this paradigm, the hunt for new therapy targets for PD has expanded. In both in-vitro and in-vivo models, the purpose of this study is to summarise the relationship between paraquat exposure and the onset of Parkinson's disease (PD).
Topics: Humans; Animals; Paraquat; Herbicides; Parkinson Disease; Parkinsonian Disorders; Dopaminergic Neurons
PubMed: 38008593
DOI: 10.1016/j.parkreldis.2023.105932 -
Life Sciences Oct 2023Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as tremors, rigidity, and bradykinesia. Current therapeutic strategies for PD are limited and mainly involve symptomatic relief, with no available treatment for the underlying causes of the disease. Therefore, there is a need for new therapeutic approaches that target the underlying pathophysiological mechanisms of PD. Calcium homeostasis is an essential process for maintaining proper cellular function and survival, including neuronal cells. Calcium dysregulation is also observed in various organelles, including the endoplasmic reticulum (ER), mitochondria, and lysosomes, resulting in organelle dysfunction and impaired inter-organelle communication. The ER, as the primary calcium reservoir, is responsible for folding proteins and maintaining calcium homeostasis, and its dysregulation can lead to protein misfolding and neurodegeneration. The crosstalk between ER and mitochondrial calcium signaling is disrupted in PD, leading to neuronal dysfunction and death. In addition, a lethal network of calcium cytotoxicity utilizes mitochondria, ER and lysosome to destroy neurons. This review article focused on the complex role of calcium dysregulation and its role in aggravating functioning of organelles in PD so as to provide new insight into therapeutic strategies for treating this disease. Targeting dysfunctional organelles, such as the ER and mitochondria and lysosomes and whole network of calcium dyshomeostasis can restore proper calcium homeostasis and improve neuronal function. Additionally targeting calcium dyshomeostasis that arises from miscommunication between several organelles can be targeted so that therapeutic effects of calcium are realised in whole cellular territory.
Topics: Humans; Parkinson Disease; Calcium; Endoplasmic Reticulum; Dopaminergic Neurons; Homeostasis
PubMed: 37541578
DOI: 10.1016/j.lfs.2023.121995 -
JCI Insight Jan 2024Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD....
Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD.
Topics: Animals; Humans; Mice; ARNTL Transcription Factors; Circadian Clocks; Dopamine; Dopaminergic Neurons; Mice, Knockout; Parkinson Disease
PubMed: 38032732
DOI: 10.1172/jci.insight.162771 -
Vaccines Dec 2023Parkinson's disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, specifically the motor system. It is mainly caused by the loss...
Parkinson's disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, specifically the motor system. It is mainly caused by the loss of dopamine due to the accumulation of α-synuclein (α-syn) protein in the striatum and substantia nigra pars compacta (SNpc). Previous studies have reported that immunization may be a potential preventive strategy for neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Therefore, the aim of the study was to design an α-syn specific epitope vaccine and investigate its effect in PD-related pathophysiology using an α-syn-induced mouse model. We used an in silico model to identify and design a non-toxic α-syn-based peptide epitope vaccine and, to overcome poor immunogenicity, the vaccine was coupled with immunogenic carrier proteins, i.e., ovalbumin (OVA) and keyhole limpet haemocyanin (KLH). Our results showed that vaccinated PD mouse models, especially with vaccines with carrier proteins, improved in motor functions compared with the non-vaccinated PD model. Additionally, the vaccinated groups showed increased immunoglobulin G (IgG) levels in the spleen and plasma as well as decreased interleukin-10 (IL-10) levels in the plasma. Furthermore, vaccinated groups, especially OVA and KLH groups, showed decrease in α-syn levels and increased dopamine-related markers, i.e., tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and dopamine transporter (DAT), and autophagy activities in the striatum and SNpc. Lastly, our data showed decreased neuroinflammation by reducing the activation of microglia and astrocytes and pro-inflammatory cytokines in the immunized groups, especially with OVA and KLH carrier proteins. Overall, these results suggest that vaccination, especially with immunogenic carrier proteins, is effective in reducing the accumulation of α-syn aggregates in the brain and ameliorate PD-related pathophysiology. Hence, further development of this approach might have a potential role in preventing the development of PD.
PubMed: 38140224
DOI: 10.3390/vaccines11121820 -
Nature Neuroscience Mar 2024Evidence of direct reciprocal connections between the cerebellum and basal ganglia has challenged the long-held notion that these structures function independently....
Evidence of direct reciprocal connections between the cerebellum and basal ganglia has challenged the long-held notion that these structures function independently. While anatomical studies have suggested the presence of cerebellar projections to the substantia nigra pars compacta (SNc), the nature and function of these connections (Cb-SNc) is unknown. Here we show, in mice, that Cb-SNc projections form monosynaptic glutamatergic synapses with dopaminergic and non-dopaminergic neurons in the SNc. Optogenetic activation of Cb-SNc axons in the SNc is associated with increased SNc activity, elevated striatal dopamine levels and increased locomotion. During behavior, Cb-SNc projections are bilaterally activated before ambulation and unilateral lever manipulation. Cb-SNc projections show prominent activation for water reward and higher activation for sweet water, suggesting that the pathway also encodes reward value. Thus, the cerebellum directly, rapidly and effectively modulates basal ganglia dopamine levels and conveys information related to movement initiation, vigor and reward processing.
Topics: Mice; Animals; Dopamine; Substantia Nigra; Locomotion; Cerebellum; Water
PubMed: 38272967
DOI: 10.1038/s41593-023-01560-9 -
NPJ Parkinson's Disease Oct 2023Loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a profound reduction of striatal dopamine are two hallmarks of Parkinson's disease (PD)....
Loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a profound reduction of striatal dopamine are two hallmarks of Parkinson's disease (PD). However, it's unclear whether degeneration starts at the neuronal soma or the striatal presynaptic terminals, and how microstructural degeneration is linked to dopaminergic loss is also uncertain. In this study, thirty de novo PD patients and twenty healthy subjects (HS) underwent 6-[F]-fluoro-L-dopa (FDOPA) PET and MRI studies no later than 12 months from clinical diagnosis. FDOPA uptake rate (K), fractional volume of free-water (FW), and iron-sensitive R2* relaxometry were quantified within nigrostriatal regions. Inter-group differences (PD vs HS) were studied using non-parametric statistics and complemented with Cohen's d effect sizes and Bayesian statistics. Correlation analyses were performed exploring biomarker dependencies and their association with bradykinesia scores. PD patients exhibited a significant decline in nigrostriatal dopaminergic activity, being post-commissural putamen (-67%) and posterolateral SNc (-11.7%) the most affected subregions within striatum and SNc respectively. Microstructural alterations (FW) were restricted to the hemisphere corresponding to the most affected side and followed similar spatial gradients as FDOPA K (+20% in posterior putamen and +11% in posterolateral SNc). R2* revealed no relevant significant changes. FDOPA and FW were correlated within the posterolateral SNc, and clinical severity was associated with FDOPA K loss. The asymmetry between striatal and SNc changes for both dopaminergic depletion and microstructural degeneration biomarkers is consistent with a neurodegenerative process that begins in the striatal terminals before progressing toward the cell bodies in the SNc.
PubMed: 37852988
DOI: 10.1038/s41531-023-00586-x -
BioRxiv : the Preprint Server For... Dec 2023Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson's disease (PD). However, the mechanisms by which intracellular aSYN...
BACKGROUND
Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson's disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain.
METHODS
aSYN PPFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell- type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser- scanning microscopy of genetically encoded sensors for bioenergetic and redox status.
RESULTS
In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure.
CONCLUSIONS
Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.
PubMed: 38168401
DOI: 10.1101/2023.12.11.571045