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International Journal of Molecular... Aug 2023Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic...
Repeated Methamphetamine Administration Results in Axon Loss Prior to Somatic Loss of Substantia Nigra Pars Compacta and Locus Coeruleus Neurons in Male but Not Female Mice.
Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic compartments of substantia nigra pars compacta (SNc) and locus coeruleus (LC) neurons. Chronic meth administration results in the degeneration of SNc and LC neurons in male mice, and MAO inhibition is neuroprotective, suggesting that the deleterious effects of chronic meth begin in axons before advancing to the soma of SNc and LC neurons. To test this hypothesis, mice were administered meth (5 mg/kg) for 14, 21, or 28 days, and SNc and LC axonal lengths and numbers of neurons were quantified. In male mice, the SNc and LC axon lengths decreased with 14, 21, and 28 days of meth, whereas somatic loss was only observed after 28 days of meth; MAO inhibition (phenelzine; 20 mg/kg) prevented axonal and somatic loss of SNc and LC neurons. In contrast, chronic (28-day) meth had no effect on the axon length or numbers of SNc or LC neurons in female mice. The results demonstrate that repeated exposure to meth produces SNc and LC axonal deficits prior to somatic loss in male subjects, consistent with a dying-back pattern of degeneration, whereas female mice are resistant to chronic meth-induced degeneration.
Topics: Male; Animals; Mice; Methamphetamine; Pars Compacta; Locus Coeruleus; Neurons; Axons; Monoamine Oxidase
PubMed: 37685846
DOI: 10.3390/ijms241713039 -
The American Journal of Pathology Mar 2016Midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta and ventral tegmental area regulate extrapyramidal movement and important cognitive functions,... (Review)
Review
Midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta and ventral tegmental area regulate extrapyramidal movement and important cognitive functions, including motivation, reward associations, and habit learning. Dysfunctions in DA neuron circuitry have been implicated in several neuropsychiatric disorders, including addiction and schizophrenia, whereas selective degeneration of DA neurons in substantia nigra pars compacta is a key neuropathological feature in Parkinson disease. Efforts to understand these disorders have focused on dissecting the underlying causes, as well as developing therapeutic strategies to replenish dopamine deficiency. In particular, the promise of cell replacement therapies for clinical intervention has led to extensive research in the identification of mechanisms involved in DA neuron development. It is hoped that a comprehensive understanding of these mechanisms will lead to therapeutic strategies that improve the efficiency of DA neuron production, engraftment, and function. This review provides a comprehensive discussion on how Wnt/β-catenin and sonic hedgehog-Smoothened signaling mechanisms control the specification and expansion of DA progenitors and the differentiation of DA neurons. We also discuss how mechanisms involving transforming growth factor-β and transcriptional cofactor homeodomain interacting protein kinase 2 regulate the survival and maturation of DA neurons in early postnatal life. These results not only reveal fundamental mechanisms regulating DA neuron development, but also provide important insights to their potential contributions to neuropsychiatric and neurodegenerative diseases.
Topics: Cell Differentiation; Dopamine; Dopaminergic Neurons; Hedgehog Proteins; Humans; Models, Biological; Motivation; Neurogenesis; Parkinson Disease; Reward; Substantia Nigra; Ventral Tegmental Area; Wnt Signaling Pathway
PubMed: 26724386
DOI: 10.1016/j.ajpath.2015.09.023 -
Bio Systems Sep 2018In this review, the author shows that ferritin has documented quantum dot material properties that have been reported in numerous independent studies, and can enable... (Review)
Review
In this review, the author shows that ferritin has documented quantum dot material properties that have been reported in numerous independent studies, and can enable quantum mechanical electron transport over substantial distances. In addition, neuromelanin is a pi-conjugated polymer, and quantum dot/pi-conjugated polymer combinations have been reported in numerous independent studies to facilitate electron transport for solar photovoltaic and other applications. Both ferritin and neuromelanin are present in large quantities in the dopamine neurons of the substantia nigra pars compactaand the norepinephrine neurons of the locus coeruleus. The unique structure of subgroups of these neurons that have a large number of axon branches and synapses may have evolved to take advantage of this electron transport mechanism, if it is present, such as to coordinate conscious action, or for other purposes. Independent clinical and laboratory studies are also reviewed that corroborate this theory of coordinated action in these neuron groups. Research to validate the theory using charge transport measurements, materials characterization, existing fluorescent probe material and reaction time testing is proposed.
Topics: Animals; Dopamine; Ferritins; Humans; Locus Coeruleus; Melanins; Neurons; Norepinephrine; Quantum Dots; Substantia Nigra
PubMed: 30048795
DOI: 10.1016/j.biosystems.2018.07.008 -
Frontiers in Cellular Neuroscience 2022Parkinson's disease (PD), a common neurodegenerative disease characterized by motor dysfunction, results from the death of dopaminergic neurons in the substantia nigra... (Review)
Review
Parkinson's disease (PD), a common neurodegenerative disease characterized by motor dysfunction, results from the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Although the precise causes of PD are still unknown, several risk factors for PD have been determined, including aging, genetic mutations, environmental factors, and gender. Currently, the molecular mechanisms underlying risk factor-related neurodegeneration in PD remain elusive. Endoplasmic reticulum stress, excessive reactive oxygen species production, and impaired autophagy have been implicated in neuronal death in the SNc in PD. Considering that these pathological processes are tightly associated with intracellular Ca, it is reasonable to hypothesize that dysregulation of Ca handling may mediate risk factors-related PD pathogenesis. We review the recent findings on how risk factors cause Ca dyshomeostasis and how aberrant Ca handling triggers dopaminergic neurodegeneration in the SNc in PD, thus putting forward the possibility that manipulation of specific Ca handling proteins and subcellular Ca homeostasis may lead to new promising strategies for PD treatment.
PubMed: 35496903
DOI: 10.3389/fncel.2022.867385 -
Genes, Brain, and Behavior Jan 2016The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the... (Review)
Review
The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson's disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, including drug addiction, autism and schizophrenia. Understanding dopamine neuron ontogeny and how dopamine connections and circuitry develops may provide us with key insights into potentially important avenues of research for other dopamine-related disorders. This review will provide a brief overview of the major molecular and genetic players throughout the development of midbrain dopamine neurons and what we know about the behavioral- and disease-related implications associated with perturbations to midbrain dopamine neuron development. We intend to combine the knowledge of two broad fields of neuroscience, both developmental and behavioral, with the intent on fostering greater discussion between branches of neuroscience in the service of addressing complex cognitive questions from a developmental perspective and identifying important gaps in our knowledge for future study.
Topics: Animals; Behavior; Dopamine; Humans; Mesencephalon; Mutation; Neurogenesis
PubMed: 26548362
DOI: 10.1111/gbb.12257 -
Neurochemistry International Jan 2023Parkinson's disease is the second most common neurodegenerative disease which is characterized by selective degeneration of dopaminergic neurons in the substantia nigra... (Review)
Review
Parkinson's disease is the second most common neurodegenerative disease which is characterized by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. The intrinsic neuronal firing activity is critical for the functional organization of brain and the specific deficits of neuronal firing activity may be associated with different brain disorders. It is known that the surviving nigra dopaminergic neurons exhibit altered firing activity, such as decreased spontaneous firing frequency, reduced number of firing neurons and increased burst firing in Parkinson's disease. Several ionic mechanisms are involved in changed firing activity of dopaminergic neurons under parkinsonian state. In this review, we summarize the changes of spontaneous firing activity as well as the possible mechanisms of nigra dopaminergic neurons in Parkinson's disease. This review may let us clearly understand the involvement of neuronal firing activity of nigra dopaminergic neurons in Parkinson's disease.
Topics: Humans; Parkinson Disease; Dopaminergic Neurons; Neurodegenerative Diseases; Substantia Nigra
PubMed: 36563966
DOI: 10.1016/j.neuint.2022.105465 -
Parkinson's Disease 2016Parkinson's disease (PD), a complex neurodegenerative disorder, is pathologically characterized by the formation of Lewy bodies and loss of dopaminergic neurons in the... (Review)
Review
Parkinson's disease (PD), a complex neurodegenerative disorder, is pathologically characterized by the formation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial dysfunction is considered to be one of the most important causative mechanisms. In addition, dysfunction of chaperone-mediated autophagy (CMA), one of the lysosomal proteolytic pathways, has been shown to play an important role in the pathogenesis of PD. An exciting and important development is recent finding that CMA and mitochondrial quality control may be linked. This review summarizes the studies revealing the link between autophagy and mitochondrial function. Discussions are focused on the connections between CMA and mitochondrial failure and on the role of MEF2D, a neuronal survival factor, in mediating the regulation of mitochondria in the context of CMA. These new findings highlight the need to further explore the possibility of targeting the MEF2D-mitochondria-CMA network in both understanding the PD pathogenesis and developing novel therapeutic strategies.
PubMed: 27413575
DOI: 10.1155/2016/2613401 -
Frontiers in Aging Neuroscience 2022Parkinson's disease (PD) is one of the most common neurodegenerative movement disorders worldwide. There are currently no cures or preventative treatments for PD.... (Review)
Review
Parkinson's disease (PD) is one of the most common neurodegenerative movement disorders worldwide. There are currently no cures or preventative treatments for PD. Emerging evidence indicates that mitochondrial dysfunction is closely associated with pathogenesis of sporadic and familial PD. Because dopaminergic neurons have high energy demand, cells affected by PD exhibit mitochondrial dysfunction that promotes the disease-defining the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The mitochondrion has a particularly important role as the cellular "powerhouse" of dopaminergic neurons. Therefore, mitochondria have become a promising therapeutic target for PD treatments. This review aims to describe mitochondrial dysfunction in the pathology of PD, outline the genes associated with familial PD and the factors related to sporadic PD, summarize current knowledge on mitochondrial quality control in PD, and give an overview of therapeutic strategies for targeting mitochondria in neuroprotective interventions in PD.
PubMed: 35795234
DOI: 10.3389/fnagi.2022.885500 -
EMBO Molecular Medicine Jun 2009The role of mitochondria in sporadic Parkinson's disease (PD) has been debated for a little over 20 years since the description of complex I deficiency in the substantia... (Review)
Review
The role of mitochondria in sporadic Parkinson's disease (PD) has been debated for a little over 20 years since the description of complex I deficiency in the substantia nigra pars compacta (SNpc) of PD patients. However, the identification of recessive pathogenic mutations in the pink1 gene in familial PD cases firmly re-ignited interest in the pathophysiology of mitochondria in PD. PINK1 is a putative mitochondrial serine/threonine kinase, which protects cells against oxidative stress induced apoptosis. The mechanism by which this is achieved and the effect of the pathogenic mutations has been an area of intensive research over the past five years. Significant progress has been made and, in this review, we summarize the physiological roles that have been assigned to PINK1 and the potential mechanisms behind pathogenesis.
Topics: Animals; Apoptosis; Biological Transport; Calcium Signaling; Disease Models, Animal; Drosophila melanogaster; Humans; Mice; Mitochondria; Models, Biological; Mutation; Neoplasms; Oxidative Stress; Parkinson Disease; Protein Folding; Protein Kinases; Ubiquitination
PubMed: 20049715
DOI: 10.1002/emmm.200900024 -
Parkinson's Disease 2016Parkinson's disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure.... (Review)
Review
Parkinson's disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure. Progressive dopaminergic neuronal cell loss in the substantia nigra pars compacta and widespread aggregation of the α-synuclein protein (encoded by the SNCA gene) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson's disease. The SNCA gene has undergone gene duplications, triplications, and point mutations. However, the specific mechanism of α-synuclein in Parkinson's disease remains obscure. Recent research showed that various α-synuclein oligomers, pathological aggregation, and propagation appear to be harmful in certain areas in Parkinson's disease patients. This review summarizes our current knowledge of the pathogenetic dysfunction of α-synuclein associated with Parkinson's disease and highlights current approaches that seek to develop this protein as a possible diagnostic biomarker and therapeutic target.
PubMed: 27610264
DOI: 10.1155/2016/1720621