Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
9.0
6.0
Journals
Cells
Special Issues
Protein Aggregation and Clearance Mechanisms in Neurodegenerative Diseases
share announcement

Protein Aggregation and Clearance Mechanisms in Neurodegenerative Diseases

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

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 24060

Special Issue Editors

Prof. Dr. Lucilla Parnetti

E-Mail Website
Guest Editor
Sezione di Neurologia, Dipartimento di Medicina e Chirurgia,Università degli Studi di Perugia, 06132 Perugia, Italy
Interests: Alzheimer's disease; Parkinson's disease; neurodegenerative diseases; cerebrospinal fluid biomarkers
Dr. Giovanni Bellomo

E-Mail Website
Guest Editor
Laboratorio di Neurochimica Clinica, Sezione di Neurologia, Dipartimento di Medicina e Chirurgia,Università degli Studi di Perugia, 06132 Perugia, Italy
Interests: Alzheimer's disease; Parkinson's disease; protein aggregation; biomarkers

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases including Alzheimer's and Parkinson's still represent a challenge for both basic and clinical research, since similar genetic and molecular profiles may result in different clinical phenotypes, and similar phenotypes may be underlined by different genetic and molecular profiles. In this respect, protein aggregation mechanisms and clearance pathways represent a hot topic, which still need to be adequately addressed and could provide in the future tools for the early diagnosis and targets for a timely treatment of these conditions.

We invite all scientists working both in basic and in applied research in the field of protein misfolding and aggregation to contribute to this Special Issue. Original research articles, reviews, or short perspective articles on all aspects related to the molecular and cellular mechanisms of protein misfolding and the diagnostics and therapy of neurodegenerative diseases are welcome.

Among the topics of interest are genetic and epigenetic profiles which confer protection or susceptibility to brain protein misfolding and aggregation, protein aggregation assays, structural properties of aggregates, protein toxicity and degradation mechanisms, novel therapeutic targets, mechanisms of resistance to therapy.

Prof. Lucilla Parnetti
Dr. Giovanni Bellomo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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

  • Protein misfolding and aggregation
  • Clearance mechanisms
  • Neurodegenerative diseases

Published Papers (6 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

19 pages, 5706 KiB  
Article
The Alpha-Synuclein RT-QuIC Products Generated by the Olfactory Mucosa of Patients with Parkinson’s Disease and Multiple System Atrophy Induce Inflammatory Responses in SH-SY5Y Cells
by Chiara Maria Giulia De Luca, Alessandra Consonni, Federico Angelo Cazzaniga, Edoardo Bistaffa, Giuseppe Bufano, Giorgia Quitarrini, Luigi Celauro, Giuseppe Legname, Roberto Eleopra, Fulvio Baggi, Giorgio Giaccone and Fabio Moda
Cells 2022, 11(1), 87; https://doi.org/10.3390/cells11010087 - 28 Dec 2021
Cited by 4 | Viewed by 3487
Abstract
Parkinson’s disease (PD) and multiple system atrophy (MSA) are caused by two distinct strains of disease-associated α-synuclein (αSynD). Recently, we have shown that olfactory mucosa (OM) samples of patients with PD and MSA can seed the aggregation of recombinant α-synuclein by [...] Read more.
Parkinson’s disease (PD) and multiple system atrophy (MSA) are caused by two distinct strains of disease-associated α-synuclein (αSynD). Recently, we have shown that olfactory mucosa (OM) samples of patients with PD and MSA can seed the aggregation of recombinant α-synuclein by means of Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC). Remarkably, the biochemical and morphological properties of the final α-synuclein aggregates significantly differed between PD and MSA seeded samples. Here, these aggregates were given to neuron-like differentiated SH-SY5Y cells and distinct inflammatory responses were observed. To deepen whether the morphological features of α-synuclein aggregates were responsible for this variable SH-SY5Y inflammatory response, we generated three biochemically and morphologically distinct α-synuclein aggregates starting from recombinant α-synuclein that were used to seed αSyn_RT-QuIC reaction; the final reaction products were used to stimulate SH-SY5Y cells. Our study showed that, in contrast to OM samples of PD and MSA patients, the artificial aggregates did not transfer their distinctive features to the αSyn_RT-QuIC products and the latter induced analogous inflammatory responses in cells. Thus, the natural composition of the αSynD strains but also other specific factors in OM tissue can substantially modulate the biochemical, morphological and inflammatory features of the αSyn_RT-QuIC products. Full article
(This article belongs to the Special Issue Protein Aggregation and Clearance Mechanisms in Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

14 pages, 3669 KiB  
Article
Night Photostimulation of Clearance of Beta-Amyloid from Mouse Brain: New Strategies in Preventing Alzheimer’s Disease
by Oxana Semyachkina-Glushkovskaya, Thomas Penzel, Inna Blokhina, Alexander Khorovodov, Ivan Fedosov, Tingting Yu, Georgy Karandin, Arina Evsukova, Dariya Elovenko, Viktoria Adushkina, Alexander Shirokov, Alexander Dubrovskii, Andrey Terskov, Nikita Navolokin, Maria Tzoy, Vasily Ageev, Ilana Agranovich, Valeria Telnova, Anna Tsven and Jürgen Kurths
Cells 2021, 10(12), 3289; https://doi.org/10.3390/cells10123289 - 24 Nov 2021
Cited by 29 | Viewed by 3146
Abstract
The deposition of amyloid-β (Aβ) in the brain is a risk factor for Alzheimer’s disease (AD). Therefore, new strategies for the stimulation of Aβ clearance from the brain can be useful in preventing AD. Transcranial photostimulation (PS) is considered a promising method for [...] Read more.
The deposition of amyloid-β (Aβ) in the brain is a risk factor for Alzheimer’s disease (AD). Therefore, new strategies for the stimulation of Aβ clearance from the brain can be useful in preventing AD. Transcranial photostimulation (PS) is considered a promising method for AD therapy. In our previous studies, we clearly demonstrated the PS-mediated stimulation of lymphatic clearing functions, including Aβ removal from the brain. There is increasing evidence that sleep plays an important role in Aβ clearance. Here, we tested our hypothesis that PS at night can stimulate Aβ clearance from the brain more effectively than PS during the day. Our results on healthy mice show that Aβ clearance from the brain occurs faster at night than during wakefulness. The PS course at night improves memory and reduces Aβ accumulation in the brain of AD mice more effectively than the PS course during the day. Our results suggest that night PS is a more promising candidate as an effective method in preventing AD than daytime PS. These data are an important informative platform for the development of new noninvasive and nonpharmacological technologies for AD therapy as well as for preventing Aβ accumulation in the brain of people with disorder of Aβ metabolism, sleep deficit, elderly age, and jet lag. Full article
(This article belongs to the Special Issue Protein Aggregation and Clearance Mechanisms in Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

22 pages, 12070 KiB  
Article
CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation
by Lea Elsholz, Yasmine Wasser, Patrick Ziegler, Pardes Habib and Aaron Voigt
Cells 2021, 10(11), 2830; https://doi.org/10.3390/cells10112830 - 21 Oct 2021
Viewed by 2186
Abstract
The pathological accumulation of α-Synuclein (α-Syn) is the hallmark of neurodegenerative α-synucleinopathies, including Parkinsons’s disease (PD). In contrast to the mostly non-phosphorylated soluble α-Syn, aggregated α-Syn is usually phosphorylated at serine 129 (S129). Therefore, S129-phosphorylation is suspected [...] Read more.
The pathological accumulation of α-Synuclein (α-Syn) is the hallmark of neurodegenerative α-synucleinopathies, including Parkinsons’s disease (PD). In contrast to the mostly non-phosphorylated soluble α-Syn, aggregated α-Syn is usually phosphorylated at serine 129 (S129). Therefore, S129-phosphorylation is suspected to interfere with α-Syn aggregation. Among other kinases, protein kinase CK1 (CK1) is known to phosphorylate α-Syn at S129. We overexpressed CK1 binding protein (CK1BP) to inhibit CK1 kinase activity. Using Bimolecular Fluorescence Complementation (BiFC) in combination with biochemical methods, we monitored the S129 phosphorylation and oligomerization of α-Syn in HEK293T cells. We found that CK1BP reduced the overall protein levels of α-Syn. Moreover, CK1BP concomitantly reduced S129 phosphorylation, oligomerization and the amount of insoluble α-Syn. Analyzing different α-Syn variants including S129 mutations, we show that the effects of CK1BP on α-Syn accumulation were independent of S129 phosphorylation. Further analysis of an aggregating polyglutamine (polyQ) protein confirmed a phosphorylation-independent decrease in aggregation. Our results imply that the inhibition of CK1 activity by CK1BP might exert beneficial effects on NDDs in general. Accordingly, CK1BP represents a promising target for the rational design of therapeutic approaches to cease or at least delay the progression of α-synucleinopathies. Full article
(This article belongs to the Special Issue Protein Aggregation and Clearance Mechanisms in Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

25 pages, 10983 KiB  
Article
Phagocytic Activities of Reactive Microglia and Astrocytes Associated with Prion Diseases Are Dysregulated in Opposite Directions
by Anshuman Sinha, Rajesh Kushwaha, Kara Molesworth, Olga Mychko, Natallia Makarava and Ilia V. Baskakov
Cells 2021, 10(7), 1728; https://doi.org/10.3390/cells10071728 - 08 Jul 2021
Cited by 11 | Viewed by 4873
Abstract
Phagocytosis is one of the most important physiological functions of the glia directed at maintaining a healthy, homeostatic environment in the brain. Under a homeostatic environment, the phagocytic activities of astrocytes and microglia are tightly coordinated in time and space. In neurodegenerative diseases, [...] Read more.
Phagocytosis is one of the most important physiological functions of the glia directed at maintaining a healthy, homeostatic environment in the brain. Under a homeostatic environment, the phagocytic activities of astrocytes and microglia are tightly coordinated in time and space. In neurodegenerative diseases, both microglia and astrocytes contribute to neuroinflammation and disease pathogenesis, however, whether their phagocytic activities are up- or downregulated in reactive states is not known. To address this question, this current study isolated microglia and astrocytes from C57BL/6J mice infected with prions and tested their phagocytic activities in live-cell imaging assays that used synaptosomes and myelin debris as substrates. The phagocytic uptake by the reactive microglia was found to be significantly upregulated, whereas that of the reactive astrocytes was strongly downregulated. The up- and downregulation of phagocytosis by the two cell types were observed irrespective of whether disease-associated synaptosomes, normal synaptosomes, or myelin debris were used in the assays, indicating that dysregulations are dictated by cell reactive states, not substrates. Analysis of gene expression confirmed dysregulation of phagocytic functions in both cell types. Immunostaining of animal brains infected with prions revealed that at the terminal stage of disease, neuronal cell bodies were subject to engulfment by reactive microglia. This study suggests that imbalance in the phagocytic activities of the reactive microglia and astrocytes, which are dysregulated in opposite directions, is likely to lead to excessive microglia-mediated neuronal death on the one hand, and the inability of astrocytes to clear cell debris on the other hand, contributing to the neurotoxic effects of glia as a whole. Full article
(This article belongs to the Special Issue Protein Aggregation and Clearance Mechanisms in Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

Review

Jump to: Research

15 pages, 4958 KiB  
Review
Waste Clearance in the Brain and Neuroinflammation: A Novel Perspective on Biomarker and Drug Target Discovery in Alzheimer’s Disease
by Kazuhiko Uchida
Cells 2022, 11(5), 919; https://doi.org/10.3390/cells11050919 - 07 Mar 2022
Cited by 11 | Viewed by 4810
Abstract
Alzheimer’s disease (AD) is a multifactorial disease with a heterogeneous etiology. The pathology of Alzheimer’s disease is characterized by amyloid-beta and hyperphosphorylated tau, which are necessary for disease progression. Many clinical trials on disease-modifying drugs for AD have failed to indicate their clinical [...] Read more.
Alzheimer’s disease (AD) is a multifactorial disease with a heterogeneous etiology. The pathology of Alzheimer’s disease is characterized by amyloid-beta and hyperphosphorylated tau, which are necessary for disease progression. Many clinical trials on disease-modifying drugs for AD have failed to indicate their clinical benefits. Recent advances in fundamental research have indicated that neuroinflammation plays an important pathological role in AD. Damage- and pathogen-associated molecular patterns in the brain induce neuroinflammation and inflammasome activation, causing caspase-1-dependent glial and neuronal cell death. These waste products in the brain are eliminated by the glymphatic system via perivascular spaces, the blood-brain barrier, and the blood–cerebrospinal fluid barrier. Age-related vascular dysfunction is associated with an impairment of clearance and barrier functions, leading to neuroinflammation. The proteins involved in waste clearance in the brain and peripheral circulation may be potential biomarkers and drug targets in the early stages of cognitive impairment. This short review focuses on waste clearance dysfunction in AD pathobiology and discusses the improvement of waste clearance as an early intervention in prodromal AD and preclinical stages of dementia. Full article
(This article belongs to the Special Issue Protein Aggregation and Clearance Mechanisms in Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

13 pages, 647 KiB  
Review
The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins
by Austin Folger and Yanchang Wang
Cells 2021, 10(11), 2835; https://doi.org/10.3390/cells10112835 - 21 Oct 2021
Cited by 11 | Viewed by 3787
Abstract
Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington’s, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine expansions are prone to aggregation. Misfolded [...] Read more.
Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington’s, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine expansions are prone to aggregation. Misfolded proteins exist as soluble monomers, small aggregates, or as large insoluble inclusion bodies. Misfolded protein aggregates are believed to be cytotoxic by stressing the protein degradation machinery, disrupting membrane structure, or sequestering other proteins. We recently showed that expression of misfolded proteins lowers cellular free ubiquitin levels, which compromises the protein degradation machinery. Therefore, the efficient degradation of misfolded proteins is critical to preserve cell health. Cells employ two major mechanisms to degrade misfolded proteins. The first is the ubiquitin-proteasome system (UPS), which ubiquitinates and degrades misfolded proteins with the assistance of segregase Cdc48/p97. The UPS pathway is mainly responsible for the clearance of misfolded proteins present as monomers or smaller aggregates. The second pathway is macroautophagy/autophagy, in which protein aggregates or inclusion bodies are recruited into an autophagosome before transport to the vacuole/lysosome for degradation. This review is focused on the current understanding of the cytotoxicity of misfolded proteins as well as their clearance pathways, with a particular emphasis on mutant Huntingtin. Full article
(This article belongs to the Special Issue Protein Aggregation and Clearance Mechanisms in Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-6
Back to TopTop