-
The New England Journal of Medicine May 2020We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in...
We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).
Topics: Aged; Animals; Basal Ganglia; Cell Differentiation; Disease Models, Animal; Dopaminergic Neurons; Follow-Up Studies; Humans; Induced Pluripotent Stem Cells; Male; Mice; Mice, SCID; Parkinson Disease; Pars Compacta; Positron-Emission Tomography; Putamen; Tomography, X-Ray Computed; Transplantation, Autologous; Transplantation, Homologous
PubMed: 32402162
DOI: 10.1056/NEJMoa1915872 -
Metabolism: Clinical and Experimental Mar 2015Sporadic or idiopathic Parkinson's disease (PD) is an age-related neurodegenerative disorder of unknown origin that ranks only second behind Alzheimer's disease (AD) in... (Review)
Review
Sporadic or idiopathic Parkinson's disease (PD) is an age-related neurodegenerative disorder of unknown origin that ranks only second behind Alzheimer's disease (AD) in prevalence and its consequent social and economic burden. PD neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta; however, more widespread involvement of other CNS structures and peripheral tissues now is widely documented. The onset of molecular and cellular neuropathology of PD likely occurs decades before the onset of the motor symptoms characteristic of PD. The hallmark symptoms of PD, resting tremors, rigidity and postural disabilities, are related to dopamine (DA) deficiency. Current therapies treat these symptoms by replacing or boosting existing DA. All current interventions have limited therapeutic benefit for disease progression because damage likely has progressed over an estimated period of ~5 to 15years to a loss of 60%-80% of the nigral DA neurons, before symptoms emerge. There is no accepted definitive biomarker of PD. An urgent need exists to develop early diagnostic biomarkers for two reasons: (1) to intervene at the onset of disease and (2) to monitor the progress of therapeutic interventions that may slow or stop the course of the disease. In the context of disease development, one of the promises of personalized medicine is the ability to predict, on an individual basis, factors contributing to the susceptibility for the development of a given disease. Recent advances in our understanding of genetic factors underlying or contributing to PD offer the potential for monitoring susceptibility biomarkers that can be used to identify at-risk individuals and possibly prevent the onset of disease through treatment. Finally, the exposome concept is new in the biomarker discovery arena and it is suggested as a way to move forward in identifying biomarkers of neurological diseases. It is a two-stage scheme involving a first stage of exposome-wide association studies (EWAS) to profile omic features in serum to discover molecular biomarkers. The second stage involves application of this knowledge base in follow-up studies. This strategy is unique in that it promotes the use of data-driven (omic) strategies in interrogating diseased and healthy populations and encourages a movement away from using only reductionist strategies to discover biomarkers of exposure and disease. In this short review we will examine 1) advances in our understanding of the molecular mechanisms underlying PD that have led to candidate biomarkers for diagnosis and treatment efficacy and 2) new technologies on the horizon that will lead to novel approaches in biomarker development.
Topics: Antiparkinson Agents; Apoptosis; Biomarkers; Disease Progression; Dopamine; Early Diagnosis; Humans; Motor Skills; Neuroimaging; Parkinson Disease; Pars Compacta; Predictive Value of Tests; Risk Factors; Sleep, REM; Smell; alpha-Synuclein
PubMed: 25510818
DOI: 10.1016/j.metabol.2014.10.030 -
CNS & Neurological Disorders Drug... 2022Parkinson's disease (PD) is the second most prominent neurodegenerative movement disorder after Alzheimer's disease, involving 2-3% of the population aged above 65... (Review)
Review
Parkinson's disease (PD) is the second most prominent neurodegenerative movement disorder after Alzheimer's disease, involving 2-3% of the population aged above 65 years. This is mainly triggered by the depletion of dopaminergic neurons located in substantia nigra pars compacta (SNpc) in the region of basal ganglia. At present, diagnosis for symptoms of PD is clinical, contextual, unspecified and therapeutically incomprehensive. Analysis of various causes of PD is essential for an accurate examination of the disease. Among the different causes, such as tremors and rigidity, unresponsiveness to the current treatment approach contributes to mortality. In the present review article, we describe various key factors of pathogenesis and physiology associated with tremors and rigidity necessary for the treatment of PI (postural instability) in patients with PD. Additionally, several reports showing early tremor and rigidity causes, particularly age, cortex lesions, basal ganglia lesions, genetic abnormalities, weakened reflexes, nutrition, fear of fall, and altered biomechanics, have been explored. By summarizing the factors that contribute to the disease, histopathological studies can assess rigidity and tremor in PD. With a clear understanding of the contributing factors, various prospective studies can be done to assess the incidence of rigidity and tremors.
Topics: Aged; Basal Ganglia; Humans; Parkinson Disease; Pars Compacta; Prospective Studies; Tremor
PubMed: 34620070
DOI: 10.2174/1871527320666211006142100 -
Fortschritte Der Neurologie-Psychiatrie Sep 2020There is consensus that the neuropathological characteristic of Parkinson's disease (PD) is the neuronal cell loss of the substantia nigra pars compacta (SNc) in... (Review)
Review
There is consensus that the neuropathological characteristic of Parkinson's disease (PD) is the neuronal cell loss of the substantia nigra pars compacta (SNc) in connection with a Lewy pathology. The transsynaptic spread of Lewy pathology is considered essential in PD pathogenesis. Therefore, the knowledge of pre-existing neuroanatomical connections of the SNc is essential. We describe recent animal experiments on the afferent and efferent projections of the SNc and discuss the evidence for and against the sequential transsynaptic spread of Lewy pathology in the pathogenesis of PD.
Topics: Animals; Humans; Parkinson Disease; Pars Compacta
PubMed: 32396943
DOI: 10.1055/a-1149-9280 -
Journal of Neural Transmission.... 2009During aging, decline in memory and cognitive abilities as well as motor weakening is of great concern. The dopaminergic system mediates some aspects of manual... (Review)
Review
During aging, decline in memory and cognitive abilities as well as motor weakening is of great concern. The dopaminergic system mediates some aspects of manual dexterity, in addition to cognition and emotion, and may be especially vulnerable to aging. A common neurodegenerative disorder of this system, Parkinson's disease, is characterized by a selective, progressive loss of dopaminergic neurons in the substantia nigra pars compacta. This review includes studies quantifying age and Parkinson's-related changes of the substantia nigra, with emphasis on stereological studies performed in the substantia nigra pars compacta.
Topics: Aging; Animals; Cell Death; Dopamine; Humans; Neurons; Parkinson Disease; Substantia Nigra; alpha-Synuclein
PubMed: 20411779
DOI: 10.1007/978-3-211-92660-4_16 -
Neurobiology of Disease Feb 2022Parkinson's disease (PD) is characterized by impaired mitochondrial function and decreased ATP levels. Aerobic glycolysis and lactate production have been shown to be...
Parkinson's disease (PD) is characterized by impaired mitochondrial function and decreased ATP levels. Aerobic glycolysis and lactate production have been shown to be upregulated in dopaminergic neurons to sustain ATP levels, but the effect of upregulated glycolysis on dopaminergic neurons remains unknown. Since lactate promotes apoptosis and α-synuclein accumulation in neurons, we hypothesized that the lactate produced upon upregulated glycolysis is involved in the apoptosis of dopaminergic neurons in PD. In this study, we examined the expression of hexokinase 2 (HK2) and lactate dehydrogenase (LDH), the key enzymes in glycolysis, and lactate levels in the substantia nigra pars compacta (SNpc) of a MPTP-induced mouse model of PD and in MPP-treated SH-SY5Y cells. We found that the expression of HK2 and LDHA and the lactate levels were markedly increased in the SNpc of MPTP-treated mice and in MPP-treated SH-SY5Y cells. Exogenous lactate treatment led to the apoptosis of SH-SY5Y cells. Intriguingly, lactate production and the apoptosis of dopaminergic neurons were suppressed by the application of 3-bromopyruvic acid (3-Brpa), a HK2 inhibitor, or siRNA both in vivo and in vitro. 3-Brpa treatment markedly improved the motor behaviour of MPTP-treated mice in pole test and rotarod test. Mechanistically, lactate increases the activity of adenosine monophosphate-activated protein kinase (AMPK) and suppresses the phosphorylation of serine/threonine kinase 1 (Akt) and mammalian target of rapamycin (mTOR). Together, our data suggest that upregulated HK2 and LDHA and increased lactate levels prompt the apoptosis of dopaminergic neurons in PD. Inhibition of HK2 expression attenuated the apoptosis of dopaminergic neurons by downregulating lactate production and AMPK/Akt/mTOR pathway in PD.
Topics: Animals; Apoptosis; Cell Line; Cell Survival; Dopaminergic Neurons; Hexokinase; Humans; L-Lactate Dehydrogenase; Lactic Acid; Mice; Motor Activity; Parkinsonian Disorders; Pars Compacta; Pyruvates; Up-Regulation
PubMed: 34973450
DOI: 10.1016/j.nbd.2021.105605 -
Metabolic Brain Disease Apr 2022Rotenone is involved in the degeneration of dopaminergic neurons, and curcumin may prevent or effectively slow the progression of Parkinson's disease (PD). Previous...
Rotenone is involved in the degeneration of dopaminergic neurons, and curcumin may prevent or effectively slow the progression of Parkinson's disease (PD). Previous research has shown that the naturally occurring phenolic compound curcumin can reduce inflammation and oxidation, making it a potential therapeutic agent for neurodegenerative diseases. The present study involves investigation of rotenone-induced histological changes in the brain area, hippocampus using Nissl staining after 35 day of subcutaneous injection of rotenone in adult male rats. We sought to determine whether curcumin could protect against rotenone-induced dopaminergic neurotoxicity in a rat model by in vivo electrical recording from Substantia nigra pars compacta (SNc). Curcumin treatment significantly improved electrical activity of neurons in the SNc of rotenone-induced PD model rats. The pattern of histological alterations corresponds with electrophysiological manifestations.
Topics: Animals; Curcumin; Dopaminergic Neurons; Male; Parkinson Disease; Pars Compacta; Rats; Rotenone; Substantia Nigra
PubMed: 35239141
DOI: 10.1007/s11011-022-00941-6 -
ACS Chemical Neuroscience Jun 2023Parkinson's disease (PD) is the second most prevailing progressive disorder leading to neurodegeneration, typically in people above 65 years of age. Motor clinical... (Review)
Review
Parkinson's disease (PD) is the second most prevailing progressive disorder leading to neurodegeneration, typically in people above 65 years of age. Motor clinical manifestations of PD appear in a much later stage and include rigidity, tremors, akinesia, and gait dysfunction. There are also nonmotor symptoms like GI and olfactory dysfunction. However, they cannot be considered for diagnosis of the disease, as they are unspecific. PD pathogenesis is mainly characterized by deposits of inclusion bodies on dopaminergic (DA) neurons in substantia nigra pars compacta region (SNpc) of the brain. The major component of these inclusion bodies, are α-synuclein aggregates. α-Synuclein undergoes misfolding and oligomerization to form aggregates and fibrils. These aggregates gradually propagate PD pathology. Other prominent features of this pathological development include mitochondrial dysfunction, neuroinflammation, oxidative stress, and impaired autophagy. These all contribute to neuronal degeneration. Besides this, there are many underlying factors which influence these processes. These factors comprise molecular proteins and signaling cascades. In this review, we have listed out underexplored molecular targets that may aid in development of neoteric and advanced therapeutics.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Pars Compacta; Dopaminergic Neurons; Brain
PubMed: 37227448
DOI: 10.1021/acschemneuro.3c00084 -
Neurobiology of Aging Mar 2023Currently, little is known about the impact of aging on astrocytes in substantia nigra pars compacta (SNpc), where dopaminergic neurons degenerate both in physiological...
Currently, little is known about the impact of aging on astrocytes in substantia nigra pars compacta (SNpc), where dopaminergic neurons degenerate both in physiological aging and in Parkinson's disease, an age-related neurodegenerative disorder. We performed a morphometric analysis of GFAP astrocytes in SNpc and, for comparison, in the pars reticulata (SNpr) of young (4-6 months), middle-aged (14-17 months) and old (20-24 months) C57BL/6J male mice. We demonstrated an age-dependent increase of structural complexity only in astrocytes localized in SNpc, and not in SNpr. Astrocytic structural remodelling was not accompanied by changes in GFAP expression, while GFAP increased in SNpr of old compared to young mice. In parallel, transcript levels of selected astrocyte-enriched genes were evaluated. With aging, decreased GLT1 expression occurred only in SNpc, while xCT transcript increased both in SNpc and SNpr, suggesting a potential loss of homeostatic control of extracellular glutamate only in the subregion where age-dependent neurodegeneration occurs. Altogether, our results support an heterogenous morphological and biomolecular response to aging of GFAP astrocytes in SNpc and SNpr.
Topics: Mice; Male; Animals; Pars Compacta; Substantia Nigra; Pars Reticulata; Astrocytes; Mice, Inbred C57BL; Aging
PubMed: 36630756
DOI: 10.1016/j.neurobiolaging.2022.12.010 -
Naunyn-Schmiedeberg's Archives of... Aug 1980Precise, bilateral radio-frequency lesions of pars compacta of the substantia nigra in rats resulted in the immediate and sustained appearance of hyperactivity, but such... (Comparative Study)
Comparative Study
Precise, bilateral radio-frequency lesions of pars compacta of the substantia nigra in rats resulted in the immediate and sustained appearance of hyperactivity, but such lesions did not produce significant alterations in food or water intake. These behavioral effects were correlated with considerable, histochemically assessed loss of dopamine terminals in the caudate-putamen complex, but dopamine innervation in nucleus accumbens and other forebrain areas was only slightly affected. The magnitude of motor activity increase was positively correlated with the degree of pars compacta involvement. Animals with lesions in the median raphe and adjacent reticular formation also displayed chronic hyperactivity. In contrast to rats receiving discrete radio-frequency lesions of pars compacta, animals with bilateral mesencephalic ablations produced by 6-hydroxydopamine (6-OHDA, 8 micrograms/4 microliters or 4 micrograms/2 microliters in combination with desipramine pretreatment) displayed poverty of movement. Furthermore, significant, dose-dependent decrements in food and water intake were seen after 6-OHDA. The nonselective component of such lesions was frequently large and irregular in shape. Occasional ablations produced by this neurotoxin, however, appeared more selective in that damage was confined primarily to pars compacta. Nonetheless, the best correlate of aphagia and adipsia associated with 6-OHDA treatment was lesion size, regardless of the extent of pars compacta or other nigral involvement. We conclude that aphagia and adipsia concomitant to 6-OHDA lesions of the substantia nigra results from the incidental destruction of extra-nigral systems. Virtually complete, but precise, lesions of pars compacta do not produce aphagia and adipsia. While our results are consistent with the notion that the substantia nigra serves an important role in the regulation of motor activity, they provide no support for the conjecture that it is importantly involved in mediating ingestive behaviors.
Topics: Animals; Body Weight; Brain Chemistry; Catecholamines; Dopamine; Drinking; Eating; Female; Microscopy, Fluorescence; Motor Activity; Radio Waves; Rats; Substantia Nigra
PubMed: 7207636
DOI: 10.1007/BF00505805