Respiratory Function and Dysfunction in Parkinson-Type Neurodegeneration

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease characterized by movement disorders due to the progressive loss of dopaminergic neurons in the ventrolateral region of the substantia nigra pars compacta (SNpc). Apart from the cardinal motor symptoms such as rigidity and bradykinesia, non-motor symptoms including those associated with respiratory dysfunction are of increasing interest. Not only can they impair the patients’ quality of life but they also can cause aspiration pneumonia, which is the leading cause of death among PD patients. This narrative review attempts to summarize the existing literature on respiratory impairments reported in human studies, as well as what is newly known from studies in animal models of the disease. Discussed are not only respiratory muscle dysfunction, apnea, and dyspnea, but also altered central respiratory control, responses to hypercapnia and hypoxia, and how they are affected by the pharmacological treatment of PD.

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“…Respiratory disturbances occurring in PD have recently attracted more interest, but their mechanisms are still not understood [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Respiratory Abnormalities in Parkinson’s Disease: What Do We Know from Studies in Humans and Animal Models?

Kaczyńska

Orłowska

Andrzejewski

2022

IJMS

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“…The potential key role of hypoxia in PD pathogenesis has been recently outlined [31] and is supported by common respiratory deficits of PD patients [32,33] as well as potentially impaired hypoxia sensing [34]. Interestingly, neuronal loss of potentially chemosensitive respiratory neurons has been demonstrated for another α-synucleinopathy, MSA [35].…”

Section: Oxygen-sensing and Consumption In Pd Brainmentioning

confidence: 93%

Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Burtscher

Millet

2021

Immuno

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Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

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“…Cytochrome P450 (CYP450) enzyme profiles and their activities in CNS cells are reported to contribute to the development of a range of NDDs. − The onset of ALS and other MNDs occurs earlier and more frequently in males than in females − and epidemiological evidence suggests that high levels of physical exercise, − smoking, − and alcohol consumption , increase the likelihood of MNDs developing in susceptible individuals. While the primary pathology associated with ALS and other MNDs is centered on the disruption of motor neuron function in the central and peripheral nervous systems, ,,− a significant number of MND/NDD cases also display liver pathology, − lung pathology, ,,− and a higher than normal incidence of cancers. ,− These very diverse characteristics and pathologies could indicate the involvement of a CYP450-activated, hepatotoxic, pneumotoxic, and broadly mutagenic factor in the initiation of some MNDs. Ideally, all the above characteristics need to be accounted for in identifying a likely environmental cause of sporadic MNDs.…”

Section: Introductionmentioning

confidence: 99%

“…When consumed in relatively high concentrations, 1,2-dehydroPAs ( 1 ) are metabolized by specific hepatic CYP450 enzymes into biological alkylating agents that cause characteristic, rapidly fatal damage to the liver and lungs (Figure ). , They also cause fatal neurotoxicity (hepatic encephalopathy) − and diverse cancers. ,,,,− Currently occurring sporadic low-level dietary exposure to 1,2-dehydroPAs is however likely to be well below levels causing these rapidly fatal, acute liver, lung, and brain pathologies but could be sufficient to eventually cause persistent genetic mutations and biochemical damage in CNS cells, leading to MNDs/NDDs that sometimes also display associated liver − and lung ,,− , pathologies and the diverse, co-occurring cancers. − , …”

Section: Introductionmentioning

confidence: 99%

1,2-Dehydropyrrolizidine Alkaloids: Their Potential as a Dietary Cause of Sporadic Motor Neuron Diseases

Edgar

Molyneux

Colegate

2022

Chem. Res. Toxicol.

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Sporadic motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), can be caused by spontaneous genetic mutations. However, many sporadic cases of ALS and other debilitating neurodegenerative diseases (NDDs) are believed to be caused by environmental factors, subject to considerable debate and requiring intensive research. A common pathology associated with MND development involves progressive mitochondrial dysfunction and oxidative stress in motor neurons and glial cells of the central nervous system (CNS), leading to apoptosis. Consequent degeneration of skeletal and respiratory muscle cells can lead to death from respiratory failure. A significant number of MND cases present with cancers and liver and lung pathology. This Perspective explores the possibility that MNDs could be caused by intermittent, low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids (1,2-dehydroPAs) that are increasingly recognized as contaminants of many foods consumed throughout the world. Nontoxic, per se, 1,2-dehydroPAs are metabolized, by particular cytochrome P450 (CYP450) isoforms, to 6,7-dihydropyrrolizines that react with nucleophilic groups (−NH, −SH, −OH) on DNA, proteins, and other vital biochemicals, such as glutathione. Many factors, including aging, gender, smoking, and alcohol consumption, influence CYP450 isoform activity in a range of tissues, including glial cells and neurons of the CNS. Activation of 1,2-dehydroPAs in CNS cells can be expected to cause gene mutations and oxidative stress, potentially leading to the development of MNDs and other NDDs. While relatively high dietary exposure to 1,2-dehydroPAs causes hepatic sinusoidal obstruction syndrome, pulmonary venoocclusive disease, neurotoxicity, and diverse cancers, this Perspective suggests that, at current intermittent, low levels of dietary exposure, neurotoxicity could become the primary pathology that develops over time in susceptible individuals, along with a tendency for some of them to also display liver and lung pathology and diverse cancers co-occurring with some MND/NDD cases. Targeted research is recommended to investigate this proposal.

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Respiratory Function and Dysfunction in Parkinson-Type Neurodegeneration

Cited by 20 publications

References 69 publications

Respiratory Abnormalities in Parkinson’s Disease: What Do We Know from Studies in Humans and Animal Models?

Respiratory Abnormalities in Parkinson’s Disease: What Do We Know from Studies in Humans and Animal Models?

Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

1,2-Dehydropyrrolizidine Alkaloids: Their Potential as a Dietary Cause of Sporadic Motor Neuron Diseases

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