Cellular and molecular pathophysiology in the progression of Parkinson’s disease

Zaman, Vandana; Shields, Donald C.; Shams, Ramsha; Drasites, Kelsey P; Matzelle, Denise; Haque, Azizul; Banik, Narendra L.

doi:10.1007/s11011-021-00689-5

Cited by 50 publications

(42 citation statements)

References 170 publications

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“…The neuro pathological hallmarks of PD are neuronal loss in the substantia nigra, which causes striatal dopaminergic deficiency, and αsynuclein accumulation in intra neuronal inclusions. However, multiple mechanisms and pathway dysfunctions play a role in the pathogenesis of PD, including oxidative stress, dysfunctional mitochon dria, cellular calcium imbalance, neuroinflammation and other neurotransmitter system deficits 1 .…”

mentioning

confidence: 99%

Parkinson disease-associated cognitive impairment

Aarsland

Batzu

Halliday

et al. 2021

Nat Rev Dis Primers

579

417

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Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting >1% of the population ≥65 years of age and with a prevalence set to double by 2030. In addition to the defining motor symptoms of PD, multiple non-motor symptoms occur; among them, cognitive impairment is common and can potentially occur at any disease stage. Cognitive decline is usually slow and insidious, but rapid in some cases. Recently, the focus has been on the early cognitive changes, where executive and visuospatial impairments are typical and can be accompanied by memory impairment, increasing the risk for early progression to dementia. Other risk factors for early progression to dementia include visual hallucinations, older age and biomarker changes such as cortical atrophy, as well as Alzheimer-type changes on functional imaging and in cerebrospinal fluid, and slowing and frequency variation on EEG. However, the mechanisms underlying cognitive decline in PD remain largely unclear. Cortical involvement of Lewy body and Alzheimer-type pathologies are key features, but multiple mechanisms are likely involved. Cholinesterase inhibition is the only high-level evidence-based treatment available, but other pharmacological and non-pharmacological strategies are being tested. Challenges include the identification of disease-modifying therapies as well as finding biomarkers to better predict cognitive decline and identify patients at high risk for early and rapid cognitive impairment.

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mentioning

confidence: 99%

Parkinson disease-associated cognitive impairment

Aarsland

Batzu

Halliday

et al. 2021

Nat Rev Dis Primers

579

417

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“…Unresolved chronic neuroinflammation can lead to neurodegeneration, which manifests by a gradual obliteration of neuronal cells. Neurodegeneration embodies the pathologies of several debilitating diseases, including multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, among others [ 12 , 13 , 14 ]. Neurodegeneration compiles both molecular and cellular events that include an accumulation of protein aggregates, modified mitochondria functions, oxidative responses, and cell death [ 1 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

RelB and Neuroinflammation

Mockenhaupt

Gonsiewski

Kordula

2021

Cells

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Neuroinflammation within the central nervous system involves multiple cell types that coordinate their responses by secreting and responding to a plethora of inflammatory mediators. These factors activate multiple signaling cascades to orchestrate initial inflammatory response and subsequent resolution. Activation of NF-κB pathways in several cell types is critical during neuroinflammation. In contrast to the well-studied role of p65 NF-κB during neuroinflammation, the mechanisms of RelB activation in specific cell types and its roles during neuroinflammatory response are less understood. In this review, we summarize the mechanisms of RelB activation in specific cell types of the CNS and the specialized effects this transcription factor exerts during neuroinflammation.

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“…Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by loss of dopamineproducing neurons in the ventral midbrain substantia nigra (SN) [1][2][3]. As the disease progresses, there exist the typical motor symptoms with bradykinesia, rigidity, impaired postural balance, a characteristic resting tremor, and consequential dementia in PD patients [4,5]. Overwhelming evidence has demonstrated that neuronal loss is linked to protein aggregation and oxidative stress [6], and especially oxidative stress is increasingly recognized as a central event contributing to the degeneration of dopaminergic neurons in the pathogenesis of PD [7].…”

Section: Introductionmentioning

confidence: 99%

“…Overwhelming evidence has demonstrated that neuronal loss is linked to protein aggregation and oxidative stress [6], and especially oxidative stress is increasingly recognized as a central event contributing to the degeneration of dopaminergic neurons in the pathogenesis of PD [7]. It is well-known that oxidative stress is due to the disequilibrium between the production of reactive oxygen species (ROS) and the availability of antioxidants or radical scavengers, which creates a perilous state contributing to cellular damage [5,8,9]. ROS are conventionally considered cytotoxic byproducts of abnormal metabolism [10].…”

Section: Introductionmentioning

confidence: 99%

“…ROS are conventionally considered cytotoxic byproducts of abnormal metabolism [10]. Excessive or sustained ROS can attack all macromolecules including lipids, proteins and nucleic acids, leading to defects in their physiological function and subsequent more ROS production and ultimately SN neuronal damage and death in PD [5,9,10]. Thus, understanding the underlying mechanisms by which oxidative stress contributes to the loss of dopaminergic neurons may help develop effective approaches in prevention and treatment of PD.…”

Section: Introductionmentioning

confidence: 99%

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NOX2-Derived Hydrogen Peroxide Impedes the AMPK/Akt-mTOR Signaling Pathway in Parkinson's Disease in Vitro Models

Zhang¹,

Zhang²,

Dong³

et al. 2021

Preprint

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Oxidative stress is closely related to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. NADPH oxidase 2 (NOX2) is involved in hydrogen peroxide (H2O2) generation. Recently, we have reported that H2O2 and PD toxins, including 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenylpyridin-1-ium (MPP+) and rotenone, induce neuronal apoptosis by inhibiting mTOR pathway. Here, we show that 6-OHDA, MPP+ or rotenone induced H2O2 generation by upregulation of NOX2 and its regulatory proteins (p22phox, p40phox, p47phox, p67phox, and Rac1), leading to apoptotic cell death in PC12 cells and primary neurons. Pretreatment with catalase, a H2O2-scavenging enzyme, significantly blocked PD toxins-evoked NOX2-derived H2O2, thereby hindering activation of AMPK, inhibition of Akt/mTOR, induction of apoptosis in neuronal cells. Similar events were also seen in the cells pretreated with Mito-TEMPO, a mitochondria-specific superoxide scavenger, implying a mitochondrial H2O2-dependent mechanism involved. Further research revealed that inhibiting NOX2 with apocynin or silencing NOX2 attenuated the effects of PD toxins on AMPK/Akt/mTOR and apoptosis in the cells. Of importance, ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPK with compound C suppressed PD toxins-induced expression of NOX2 and its regulatory proteins, as well as consequential H2O2 and apoptosis in the cells. Taken together, these results indicate that certain PD toxins can impede the AMPK/Akt-mTOR signaling pathway leading to neuronal apoptosis by eliciting NOX2-derived H2O2. Our findings suggest that neuronal loss in PD may be prevented by regulating of NOX2, AMPK/Akt-mTOR signaling and/or administering antioxidants to ameliorate oxidative stress.

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Cellular and molecular pathophysiology in the progression of Parkinson’s disease

Cited by 50 publications

References 170 publications

Parkinson disease-associated cognitive impairment

Parkinson disease-associated cognitive impairment

RelB and Neuroinflammation

NOX2-Derived Hydrogen Peroxide Impedes the AMPK/Akt-mTOR Signaling Pathway in Parkinson's Disease in Vitro Models

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