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Cells
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The Cell Biology of Parkinson’s Disease
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The Cell Biology of Parkinson’s Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 16633

Special Issue Editor

Prof. Dr. Wolfgang Jost

E-Mail Website
Guest Editor
Parkinson-Klinik Ortenau GmbH, 77709 Wolfach, Germany
Interests: botulinum toxin; dystonia; cervical dystonia; sialorrhea; Parkinson’s disease; Blepharospasm
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the field of medicine, the saying has long been accepted that “Whoever heals is right”. Those of us in this field have also been smiled at condescendingly from workers in basic science because as clinicians we work with the principle of trial and error and then subsequently construct the appropriate theory.

This principle of work has been abandoned successively in recent years in such a way that the two positions (clinical vs. basic) have been approximating each other more and more. Nonetheless, a good number of clinical studies are still based on limited theoretical fundaments. This is due, among other things, to the fact that we have patients who are suffering considerably from the symptoms of their disease and who thus just cannot wait. As clinicians, we have to live with our deficits and still at the same time minimize them. A further problem arises when individual clinicians do not yet comprehend the theoretical approaches or even need to understand them and when, vice versa, basic scientists are less familiar with clinical topics. This deep divide has admittedly become less formidable through the last few decades, but it is still effective and leads to misunderstandings and, even worse, to distrust. Such miscommunication can only be dispelled by constantly addressing the possibility of these problems with colleagues. A win–win situation is within reach.

With our Special Issue, we hope to contribute to improving our understanding of each other’s differing positions. This is the only way to understand and improve our respective efforts and to thereby develop new and worthwhile approaches. Every one of us, as a basic researcher or clinician, is of course allowed to dream and be creative, but must adhere to the rules. Together, we can develop appropriate steps forward, not only to our own advantage but also to the full advantage of our patients.

Prof. Dr. Wolfgang Jost
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Parkinson's disease
  • basal ganglia
  • dopamine
  • degeneration

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Published Papers (3 papers)

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Research

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10 pages, 1929 KiB  
Article
Brain Noradrenergic Innervation Supports the Development of Parkinson’s Tremor: A Study in a Reserpinized Rat Model
by Nicoló Gabriele Pozzi, Francesco Bolzoni, Gabriele Eliseo Mario Biella, Gianni Pezzoli, Chi Wang Ip, Jens Volkmann, Paolo Cavallari, Esther Asan and Ioannis Ugo Isaias
Cells 2023, 12(21), 2529; https://doi.org/10.3390/cells12212529 - 27 Oct 2023
Cited by 2 | Viewed by 1361
Abstract
The pathophysiology of tremor in Parkinson’s disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. [...] Read more.
The pathophysiology of tremor in Parkinson’s disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um2, p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic–rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients. Full article
(This article belongs to the Special Issue The Cell Biology of Parkinson’s Disease)
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20 pages, 4805 KiB  
Article
S-nitrosylated PARIS Leads to the Sequestration of PGC-1α into Insoluble Deposits in Parkinson’s Disease Model
by Hanna Kim, Ji-Yeong Lee, Soo Jeong Park, Eunsang Kwag, Jihye Kim and Joo-Ho Shin
Cells 2022, 11(22), 3682; https://doi.org/10.3390/cells11223682 - 19 Nov 2022
Cited by 6 | Viewed by 2533
Abstract
Neuronal accumulation of parkin-interacting substrate (PARIS), a transcriptional repressor of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), has been observed in Parkinson’s disease (PD). Herein, we showed that PARIS can be S-nitrosylated at cysteine 265 (C265), and S-nitrosylated PARIS (SNO-PARIS) translocates to the [...] Read more.
Neuronal accumulation of parkin-interacting substrate (PARIS), a transcriptional repressor of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), has been observed in Parkinson’s disease (PD). Herein, we showed that PARIS can be S-nitrosylated at cysteine 265 (C265), and S-nitrosylated PARIS (SNO-PARIS) translocates to the insoluble fraction, leading to the sequestration of PGC-1α into insoluble deposits. The mislocalization of PGC-1α in the insoluble fraction was observed in S-nitrosocysteine-treated PARIS knockout (KO) cells overexpressing PARIS WT but not S-nitrosylation deficient C265S mutant, indicating that insolubility of PGC-1α is SNO-PARIS-dependent. In the sporadic PD model, α-synuclein preformed fibrils (α-syn PFFs)-injected mice, we found an increase in PARIS, SNO-PARIS, and insoluble sequestration of PGC-1α in substantia nigra (SN), resulting in the reduction of mitochondrial DNA copy number and ATP concentration that were restored by N(ω)-nitro-L-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor. To assess the dopaminergic (DA) neuronal toxicity by SNO-PARIS, lentiviral PARIS WT, C265S, and S-nitrosylation mimic C265W was injected into the SN of either PBS- or α-syn PFFs-injected mice. PARIS WT and C265S caused DA neuronal death to a comparable extent, whereas C265W caused more severe DA neuronal loss in PBS-injected mice. Interestingly, there was synergistic DA loss in both lenti-PARIS WT and α-syn PFFs-injected mice, indicating that SNO-PARIS by α-syn PFFs contributes to the DA toxicity in vivo. Moreover, α-syn PFFs-mediated increment of PARIS, SNO-PARIS, DA toxicity, and behavioral deficits were completely nullified in neuronal NOS KO mice, suggesting that modulation of NO can be a therapeutic for α-syn PFFs-mediated neurodegeneration. Full article
(This article belongs to the Special Issue The Cell Biology of Parkinson’s Disease)
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Review

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38 pages, 5010 KiB  
Review
NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease
by William M. Curtis, William A. Seeds, Mark P. Mattson and Patrick C. Bradshaw
Cells 2022, 11(15), 2416; https://doi.org/10.3390/cells11152416 - 4 Aug 2022
Cited by 25 | Viewed by 11770
Abstract
Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson’s disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion [...] Read more.
Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson’s disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD. Full article
(This article belongs to the Special Issue The Cell Biology of Parkinson’s Disease)
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