Life on the Edge: Determinants of Selective Neuronal Vulnerability in Parkinson’s Disease

Surmeier, James D.; Zampese, Enrico; Galtieri, Daniel; Schumacker, Paul T.

doi:10.1007/978-3-319-28637-2_6

Cited by 3 publications

(2 citation statements)

References 255 publications

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“…Similar to the proposal by Braak et al 2003 [20], Sulzer and Surmeier [35] postulated that energy demands play a major role in the cell vulnerabilities underlying PD, but instead of the focus on poor myelination, they focused on the energy burdens on the cell body of maintaining a massive axon system and continuous firing (autonomous pacemaking). Surmeier especially strongly expressed PD vulnerability via high bioenergetic demands in a presentation in 2016, in which the type of sustained (tonic) firing by SNc DA neurons (see below) was considered "bioenergetically expensive" and to cause these cells to be "close to a bioenergetic cliff" [84]. Also, in later studies, when discussing PD vulnerability, the Surmeier group kept emphasizing that "SN DA neurons have a high basal bioenergetic demand" [81], which may be true but at least deserves some nuance as the demand may not be higher than in PD-resistant neurons (see below).…”

Section: Some Critical Considerationsmentioning

confidence: 99%

Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges

Watanabe,

Dijkstra,

Nagatsu

2024

IJMS

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The core pathological event in Parkinson’s disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

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Section: Some Critical Considerationsmentioning

confidence: 99%

Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges

Watanabe,

Dijkstra,

Nagatsu

2024

IJMS

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“…This formation of the lewy Bodies leads to the loss of neurons and this cause Parkinson's disease 1 . Parkinson's disease is the most common neurodegenerative disease, which affects life span of the elder people.…”

Section: Introductionmentioning

confidence: 99%

Untitled

2018

IJPSR

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Neurodegenerative disease is the condition of brain cells that lose of its ability to generate the neurotransmitters and this leads to the accumulation of proteins in the brain. These condition causes memory loss and problems in the cognitive functions. Neurological diseases are characterized by four major types such as Alzheimer's disease, Parkinson's disease, Huntington disease, Amyotrophic lateral sclerosis. Parkinson's disease is a second neurological disorder, characterized by a selective loss of dopaminergic neurons in the substantianigra, causing a subsequent reduction of dopamine levels in the striatum. Loss of dopaminergic neurons in striatum causes imbalance of neurotransmitters like acetylcholine and dopamine, resulting in the Parkinson's disease. Tremor, rigidity, dyskinesia are the primary symptoms and memory loss, sleeps disorders, cognitive impairments are the secondary symptoms of Parkinson's. Aim: To investigate the structural changes in silico docking was performedwith target protein LRRK2 with the following compounds theaflavin, baicalein, sesamol, tenuigenin, gastrodin, phloroglucinol and L-DOPA. Methods: The in silico docking was carried out using autodock version 4.2. Rasmol tool was used to visualize the protein structures. Results: The docking energy of L-DOPA with LRRK2 showed binding energy-4.97 Kcal/mol, Kcal/ mol, gastrodin-6.02 Kcal/mol and phloroglucinol as binding energy-4.99 Kcal/mol. Conclusion: These results indicate that the natural plant compounds have more affinity and interact with LRRK2 in a better manner compared to the L-DOPA the standard drug. Therefore natural plant compounds may be helpful in the treatment of Parkinson's disease.

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Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-related Oxidative Stress and Other Bioenergetic Challenges

Watanabe,

Dijkstra,

Nagatsu

2024

Preprint

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The core pathological event in Parkinson’s disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans is still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple of the risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

show abstract

Life on the Edge: Determinants of Selective Neuronal Vulnerability in Parkinson’s Disease

Cited by 3 publications

References 255 publications

Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges

Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges

Untitled

Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-related Oxidative Stress and Other Bioenergetic Challenges

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