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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 -
The FEBS Journal Oct 2018The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha-synuclein... (Review)
Review
The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha-synuclein (aSYN) pathology and mitochondrial dysfunction have been implicated in PD pathogenesis, but until recently it was unclear why SNc dopaminergic neurons should be particularly vulnerable to these two types of insult. In this brief review, the evidence that SNc dopaminergic neurons have an anatomical, physiological, and biochemical phenotype that predisposes them to mitochondrial dysfunction and synuclein pathology is summarized. The recognition that certain traits may predispose neurons to PD-linked pathology creates translational opportunities for slowing or stopping disease progression.
Topics: Animals; Calcium; Dopaminergic Neurons; Humans; Mitochondria; Oxidative Stress; Parkinson Disease; alpha-Synuclein
PubMed: 30028088
DOI: 10.1111/febs.14607 -
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 -
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 -
Neurosciences (Riyadh, Saudi Arabia) Jan 2023Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the... (Review)
Review
Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc). Current therapeutic options ease the symptoms of PD; however, they have multiple undesirable effects and do not slow the disease progression. Exercise by itself has many positive impacts on general health. In this review, the positive impact of different forms of exercise were found to improve motor and non-motor symptoms in PD. Exercise effects is mediate by multiple mechanisms, including the upregulation of brain-derived neurotrophic factor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and autophagy regulating proteins; and downregulates proinflammatory cytokines. In this review, the significance of exercise in PD, as well as in the prevention and maintenance of the disease was discussed. Many questions are left unanswered in this manuscript, including potential genetic factors underlying response to exercise. Therefore, further high-quality studies on humans are needed.
Topics: Humans; Animals; Parkinson Disease; Dopamine; Exercise; Dopaminergic Neurons; Disease Models, Animal
PubMed: 36617448
DOI: 10.17712/nsj.2023.1.20220105 -
Brain : a Journal of Neurology Dec 2023Although neuromelanin is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta, its potential role in the pathogenesis of...
Although neuromelanin is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta, its potential role in the pathogenesis of Parkinson's disease (PD) has often been neglected since most commonly used laboratory animals lack neuromelanin. Here we took advantage of adeno-associated viral vectors encoding the human tyrosinase gene for triggering a time-dependent neuromelanin accumulation within substantia nigra pars compacta dopaminergic neurons in macaques up to similar levels of pigmentation as observed in elderly humans. Furthermore, neuromelanin accumulation induced an endogenous synucleinopathy mimicking intracellular inclusions typically observed in PD together with a progressive degeneration of neuromelanin-expressing dopaminergic neurons. Moreover, Lewy body-like intracellular inclusions were observed in cortical areas of the frontal lobe receiving dopaminergic innervation, supporting a circuit-specific anterograde spread of endogenous synucleinopathy by permissive trans-synaptic templating. In summary, the conducted strategy resulted in the development and characterization of a new macaque model of PD matching the known neuropathology of this disorder with unprecedented accuracy. Most importantly, evidence is provided showing that intracellular aggregation of endogenous α-synuclein is triggered by neuromelanin accumulation, therefore any therapeutic approach intended to decrease neuromelanin levels may provide appealing choices for the successful implementation of novel PD therapeutics.
Topics: Animals; Humans; Aged; Synucleinopathies; Substantia Nigra; alpha-Synuclein; Parkinson Disease; Primates
PubMed: 37769648
DOI: 10.1093/brain/awad331 -
International Journal of Molecular... May 2023Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease,... (Review)
Review
Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis in different diseases, animal modeling is customized and specific accordingly. As in other neurodegenerative diseases, Parkinson's disease is a progressive disorder coupled with varying forms of physical and mental disabilities. The pathological hallmarks of Parkinson's disease are associated with the accumulation of misfolded protein called α-synuclein as Lewy body, and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) area affecting the patient's motor activity. Extensive research has already been conducted regarding animal modeling of Parkinson's diseases. These include animal systems with induction of Parkinson's, either pharmacologically or via genetic manipulation. In this review, we will be summarizing and discussing some of the commonly employed Parkinson's disease animal model systems and their applications and limitations.
Topics: Animals; Parkinson Disease; alpha-Synuclein; Pars Compacta; Lewy Bodies; Disease Models, Animal; Dopaminergic Neurons; Substantia Nigra
PubMed: 37240432
DOI: 10.3390/ijms24109088 -
Frontiers in Human Neuroscience 2016As Parkinson's disease progresses, a massive loss of dopaminergic neurons is accompanied by accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy... (Review)
Review
As Parkinson's disease progresses, a massive loss of dopaminergic neurons is accompanied by accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies and Lewy neurites. Inclusions first appear in olfactory bulb and enteric neurons then in ascendant neuroanatomical interconnected areas, and finally, in late stages of the disease, Lewy bodies are observed in a substantia nigra pars compacta with clear signs of neuronal loss. It is believed that the spreading of Lewy bodies through the nervous system is a consequence of the cell-to-cell propagation of αSyn, that can occur via sequential steps of secretion and uptake. Certain pathological forms of transmitted αSyn are able to seed endogenous counterparts in healthy recipient cells, thus promoting the self-sustained cycle of inclusion formation, amplification and spreading, that ultimately underlies disease progression. Here we review the cell-to-cell propagation of αSyn focusing on its role in the progression of Parkinson's disease.
PubMed: 27994545
DOI: 10.3389/fnhum.2016.00608