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European Journal of Neurology Feb 2024The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the...
BACKGROUND AND PURPOSE
The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN.
METHODS
A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat-primed PCR and GC-rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno-associated virus (AAV)-mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection.
RESULTS
Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p-value = 0.29). Skin biopsy showed P62-positive intranuclear NOTCH2NLC-polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa-NOTCH2NLC-(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN.
CONCLUSIONS
Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons.
Topics: Animals; Humans; Mice; Dopaminergic Neurons; Intranuclear Inclusion Bodies; Mice, Transgenic; Nerve Degeneration; Parkinson Disease; Substantia Nigra; Trinucleotide Repeat Expansion
PubMed: 37975799
DOI: 10.1111/ene.16145 -
Analytical Cellular Pathology... 2021An increasing number of people are in a state of stress due to social and psychological pressures, which may result in mental disorders. Previous studies indicated that...
An increasing number of people are in a state of stress due to social and psychological pressures, which may result in mental disorders. Previous studies indicated that mesencephalic dopaminergic neurons are associated with not only reward-related behaviors but also with stress-induced mental disorders. To explore the effect of stress on dopaminergic neuron and potential mechanism, we established stressed rat models of different time durations and observed pathological changes in dopaminergic neurons of the ventral tegmental area (VTA) through HE and thionine staining. Immunohistochemistry coupled with microscopy-based multicolor tissue cytometry (MMTC) was employed to investigate the number changes of dopaminergic neurons. Double immunofluorescence labelling was used to investigate expression changes of endoplasmic reticulum stress (ERS) protein GRP78 and CHOP in dopaminergic neurons. Our results showed that prolonged stress led to pathological alteration in dopaminergic neurons of VTA, such as missing of Nissl bodies and pyknosis in dopaminergic neurons. Immunohistochemistry with MMTC indicated that chronic stress exposure resulted in a significant decrease in dopaminergic neurons. Double immunofluorescence labelling showed that the endoplasmic reticulum stress protein took part in the injury of dopaminergic neurons. Taken together, these results indicated the involvement of ERS in mesencephalic dopaminergic neuron injury induced by stress exposure.
Topics: Animals; Cell Death; Disease Models, Animal; Dopaminergic Neurons; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Male; Nissl Bodies; Rats, Sprague-Dawley; Stress, Psychological; Transcription Factor CHOP; Ventral Tegmental Area; Rats
PubMed: 34540569
DOI: 10.1155/2021/7852710 -
Aging May 2020Long non-coding RNAs (lncRNA) and microRNAs (miRNAs) are a subject of active investigation in neurodegenerative disorders including Parkinson's disease (PD). We...
Long non-coding RNAs (lncRNA) and microRNAs (miRNAs) are a subject of active investigation in neurodegenerative disorders including Parkinson's disease (PD). We hypothesized a regulatory role of lncRNA H19 with involvement of hypoxanthine phosphoribosyltransferase 1 (HPRT1) in dopaminergic neuron loss in PD model mice obtained by 6-hydroxydopamine (6-OHDA) lesions. We predicted the differentially expressed genes and related mechanisms by microarray analysis. We measured the expression of tyrosine hydroxylase (TH) and proneural genes in the substantia nigra of lesioned mice before and after treatment with lentiviral oe-HPRT1, agomir-miR-301b-3p and inhibition of the Wnt/β-catenin pathway. We also evaluated the relationship among lncRNA H19, HPRT1 and miR-301b-3p as well as the Wnt/β-catenin signaling pathway in these mice. The obtained results predicted and further confirmed a low level of HPRT1 in lesioned mice. We found low expression of lncRNA H19 and showed that its forced overexpression regulated HPRT1 by binding to miR-301b-3p. The overexpression of HPRT1 increased TH expression and inhibited dopaminergic neuron loss activating the Wnt/β-catenin pathway, as reflected by increased expressions of Nurr-1, Pitx-3, Ngn-2 and NeuroD1. Thus, overexpressed lncRNA H19 protects against dopaminergic neuron loss in this PD model through activating the Wnt/β-catenin pathway impairing miR-301b-3p-targeted inhibition of HPRT1 expression.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Hypoxanthine Phosphoribosyltransferase; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Parkinson Disease; RNA, Long Noncoding; Substantia Nigra; Wnt Signaling Pathway
PubMed: 32434961
DOI: 10.18632/aging.102877 -
Biochemical and Biophysical Research... Jun 2022Motivational states are important determinants of behavior. In Drosophila melanogaster, courtship behavior is robust and crucial for species continuation. However, the...
Motivational states are important determinants of behavior. In Drosophila melanogaster, courtship behavior is robust and crucial for species continuation. However, the motivation of courtship behavior remains unexplored. We first find the phenomenon that courtship behavior is modulated by motivational state. A male fly courts another male fly when it first courts a decapitated female fly, however, male-male courtship behavior rarely occurs under normal conditions. Therefore, in this phenomenon, the male fly's courtship motivational state is induced by its exposure to female flies. Blocking dopaminergic neurons synaptic transmission by expressing Tetanus toxin light chain (TNTe) decreases motivational state induced male-male courtship behavior without affecting male-female courtship behavior. Vision cues are another key component in sexually driven Drosophila male-male courtship behavior. Here, we identify a base theory that the inner motivational state could eventually decide Drosophila behavior.
Topics: Animals; Courtship; Dopaminergic Neurons; Drosophila; Drosophila Proteins; Drosophila melanogaster; Female; Male; Motivation; Sexual Behavior, Animal
PubMed: 35430448
DOI: 10.1016/j.bbrc.2022.04.025 -
Annals of Neurology Mar 2017Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma...
OBJECTIVE
Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss-of-function variants of MC1R have also been linked to increased risk of Parkinson disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo.
METHODS
Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures.
RESULTS
MC1R mice, which carry an inactivating mutation of MC1R and mimic the human redhead phenotype, have compromised nigrostriatal dopaminergic neuronal integrity, and they are more susceptible to dopaminergic neuron toxins 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, a selective MC1R agonist protects against MPTP-induced dopaminergic neurotoxicity.
INTERPRETATION
Our findings reveal a protective role of MC1R in the nigrostriatal dopaminergic system, and they provide a rationale for MC1R as a potential therapeutic target for Parkinson disease. Together with its established role in melanoma, MC1R may represent a common pathogenic pathway for melanoma and Parkinson disease. Ann Neurol 2017;81:395-406.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Disease Models, Animal; Dopaminergic Neurons; Humans; Male; Melanoma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neostriatum; Neurotoxins; Parkinson Disease; Pigmentation; Receptor, Melanocortin, Type 1; Substantia Nigra
PubMed: 28019657
DOI: 10.1002/ana.24852 -
International Journal of Molecular... Apr 2022The degeneration of nigral dopaminergic neurons is considered the hallmark of Parkinson's disease (PD), and it is triggered by different factors, including mitochondrial... (Review)
Review
The degeneration of nigral dopaminergic neurons is considered the hallmark of Parkinson's disease (PD), and it is triggered by different factors, including mitochondrial dysfunction, Lewy body accumulation, neuroinflammation, excitotoxicity and metal accumulation. Despite the extensive literature devoted to unravelling the signalling pathways involved in neuronal degeneration, little is known about the functional impairments occurring in these cells during illness progression. Of course, it is not possible to obtain direct information on the properties of the dopaminergic cells in patients. However, several data are available in the literature reporting changes in the function of these cells in PD animal models. In the present manuscript, we focus on dopaminergic neuron functional properties and summarize shared or peculiar features of neuronal dysfunction in different PD animal models at different stages of the disease in an attempt to design a picture of the functional modifications occurring in nigral dopaminergic neurons during disease progression preceding their eventual death.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra; alpha-Synuclein
PubMed: 35562898
DOI: 10.3390/ijms23094508 -
Neuropathology : Official Journal of... Apr 2022Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive movement disability accompanied by non-motor symptoms. The neuropathology hallmark... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive movement disability accompanied by non-motor symptoms. The neuropathology hallmark of PD is the loss of dopaminergic neurons predominantly in the substantia nigra pars compacta and the presence of intracellular inclusions termed Lewy bodies (LBs), which are mainly composed of α-synuclein (αSyn). Detailed staging based on the distribution and progression pattern of αSyn pathology in the postmortem brains of PD patients revealed correlation with the clinical phenotypes but not invariably. Cumulative evidence from cell and animal studies has implied that αSyn propagation contributes to the anatomical spread of αSyn pathology in the brain. Here, we recount the studies over the past two centuries on the anatomopathological foundations of PD documented. We also review studies on the structural analysis of αSyn and LBs, Braak staging of αSyn pathology, the cell-to-cell propagation of αSyn as well as αSyn fibril polymorphisms, which underlie the phenotypic differences in synucleinopathies.
Topics: Animals; Dopaminergic Neurons; Humans; Lewy Bodies; Neuropathology; Parkinson Disease; alpha-Synuclein
PubMed: 35362115
DOI: 10.1111/neup.12812 -
Midbrain dopaminergic neuron activity across alternating brain states of urethane anaesthetized rat.The European Journal of Neuroscience Apr 2017Midbrain dopaminergic neurons are implicated in the control of motor functions and reward-driven behaviours. The function of this neuronal population is strongly...
Midbrain dopaminergic neurons are implicated in the control of motor functions and reward-driven behaviours. The function of this neuronal population is strongly connected with distinct patterns of firing - irregular or bursting, which either maintains basal levels of dopamine (DA) or leads to phasic release, respectively. Heterogeneity of dopaminergic neurons, observed on both structural and functional levels, is also reflected in different responses of DA neurons to changes in global brain states. Preparation of urethane anaesthetized animal is a broadly used model to study brain state dependent activity of neurons. Unfortunately activity of midbrain DA neurons across urethane induced cyclic, spontaneous brain state alternations is poorly described. To fulfil this gap in our knowledge we have performed simultaneous, extracellular recordings of the firing of single putative DA neurons combined with continuous brain state monitoring. We found that during slow wave activity, the firing rate of recorded putative DA neurons was significantly higher compared to firing rates during activated state, both in ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). In the presence of cortical slow waves, putative dopaminergic neurons also intensified bursting activity, but the magnitude of this phenomena differed in respect to the examined region (VTA or SNc). Our results show that activity of DA neurons under urethane anaesthesia is brain-state dependent and emphasize the importance of brain state monitoring during electrophysiological experiments.
Topics: Action Potentials; Anesthesia; Anesthetics, Intravenous; Animals; Brain Waves; Dopaminergic Neurons; Electrocorticography; Male; Mesencephalon; Microelectrodes; Rats, Wistar; Urethane
PubMed: 28177164
DOI: 10.1111/ejn.13533 -
Frontiers in Bioscience (Elite Edition) Jan 2013Substantial evidence indicates that neuroinflammation caused by microglial activation in substantia nigra is critical in the pathogenesis of dopaminergic...
Substantial evidence indicates that neuroinflammation caused by microglial activation in substantia nigra is critical in the pathogenesis of dopaminergic neurodegeneration in Parkinson's disease (PD). Increasing data demonstrates that environmental factors such as rotenone, paraquat play pivotal roles in dopaminergic neuron death. Here, potential role and mechanism of neuromelanin (NM), a major endogenous component in dopaminergic neurons of substantia nigra, on microglial activation and associated dopaminergic neurotoxicity were investigated. Using multiple primary mesencephalic cultures, we found that HNM caused dopaminergic neurodegeneration characterized by the decreased dopamine uptake and reduced numbers and shorted dendrites. HNM was selectively toxic to dopaminergic neurons since the other types of neurons determined by either gamma-aminobutyric acid uptake and total neuronal numbers showed smaller decrease. HNM produced modest dopaminergic neurotoxicity in neuron-enriched cultures; in contrast, much greater neurotoxicity was observed in the presence of microglia. HNM morphologically activated microglia and produced proinflammatory and neurotoxic factors. Thus, HNM can be a potent endogenous activator of microglial reactivation, mediating PD progression. Hence, inhibition of microglial reactivation can be a useful strategy for PD therapy.
Topics: Analysis of Variance; Animals; Cell Death; Cells, Cultured; Dendrites; Dopamine; Dopaminergic Neurons; Female; Humans; Immunohistochemistry; Melanins; Microglia; Nitric Oxide; Parkinson Disease; Pregnancy; Rats; Substantia Nigra; Tumor Necrosis Factor-alpha
PubMed: 23276965
DOI: 10.2741/e591 -
Brain : a Journal of Neurology Sep 2017Loss of function mutations in the gene PARK2, which encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, a neurodegenerative disease... (Review)
Review
Loss of function mutations in the gene PARK2, which encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, a neurodegenerative disease characterized by degeneration of the dopaminergic neurons localized in the substantia nigra pars compacta. No therapy is effective in slowing disease progression mostly because the pathogenesis of the disease is yet to be understood. From accruing evidence suggesting that the protein parkin directly regulates synapses it can be hypothesized that PARK2 gene mutations lead to early synaptic damage that results in dopaminergic neuron loss over time. We review evidence that supports the role of parkin in modulating excitatory and dopaminergic synapse functions. We also discuss how these findings underpin the concept that autosomal recessive juvenile parkinsonism can be primarily a synaptopathy. Investigation into the molecular interactions between parkin and synaptic proteins may yield novel targets for pharmacologic interventions.
Topics: Animals; Dopaminergic Neurons; Humans; Mutation; Nerve Degeneration; Parkinson Disease; Synaptic Transmission; Ubiquitin-Protein Ligases
PubMed: 28335015
DOI: 10.1093/brain/awx006