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Proteotoxicity and Neurodegenerative Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 53126

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Dr. Gessica Sala

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Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Milan, Italy
Interests: study of pathogenic mechanisms (proteotoxicity, autophagy dysfunctions, oxidative stress, excitotoxicity) and discovery of biomarkers in neurodegenerative diseases using ex vivo peripheral cells from patients and in vitro disease models
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Prof. Dr. Lucio Tremolizzo

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1. School of Medicine and Surgery, Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Monza (MB), Italy
2. Departmentof Neurology, San Gerardo Hospital, Monza (MB), Italy
Interests: neurodegenerative diseases; amyotrophic lateral sclerosis; dementia, oxidative stress; excitotoxicity; peripheral cells; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Many neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS) belong to the large category of proteinopathies, conditions characterized by the presence of proteinaceous inclusions within and/or outside the degenerating neurons. The identification of such aggregates supports the view that misfolded proteins represent a basic requirement for the neurodegenerative process and provides input to verify the existence of possible dysfunctions of the biological systems influencing protein homeostasis.

In neurodegenerative diseases, both environmental and genetic factors contribute to altering the physiological processes involved in the synthesis of disease-specific proteins, resulting in a protein over-production or in the generation of post-translationally modified protein forms more prone to aggregation. Furthermore, the impairment of intracellular protein catabolic systems plays a crucial role in proteotoxicity, and the prion-like spreading of pathological proteins further amplifies neuronal damage.

A better comprehension of the molecular mechanisms responsible for proteotoxicity in neurodegenerative diseases can allow the identification of both new therapeutic targets and useful biomarkers for these devastating disorders.

Dr. Gessica Sala
Prof. Dr. Lucio Tremolizzo
Guest Editors

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Keywords

Parkinson’s disease
amyotrophic lateral sclerosis
Alzheimer’s disease
neurodegenerative diseases
alpha-synuclein
TDP-43
beta-amyloid
tau
genetics
catabolism

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Published Papers (10 papers)

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Research

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17 pages, 2529 KiB

Open AccessArticle

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer’s Disease Pathology in 5xFAD Model Mice

by Malena dos Santos Guilherme, Victor F. Zevallos, Aline Pesi, Nicolai M. Stoye, Vu Thu Thuy Nguyen, Konstantin Radyushkin, Andreas Schwiertz, Ulrich Schmitt, Detlef Schuppan and Kristina Endres

Int. J. Mol. Sci. 2020, 21(17), 6288; https://doi.org/10.3390/ijms21176288 - 31 Aug 2020

Cited by 14 | Viewed by 4487

Abstract

Wheat amylase trypsin inhibitors (ATIs) represent a common dietary protein component of gluten-containing cereals (wheat, rye, and barley). They act as toll-like receptor 4 ligands, and are largely resistant to intestinal proteases, eliciting a mild inflammatory response within the intestine after oral ingestion. Importantly, nutritional ATIs exacerbated inflammatory bowel disease and features of fatty liver disease and the metabolic syndrome in mice. For Alzheimer’s disease (AD), both inflammation and altered insulin resistance are major contributing factors, impacting onset as well as progression of this devastating brain disorder in patients. In this study, we evaluated the impact of dietary ATIs on a well-known rodent model of AD (5xFAD). We assessed metabolic, behavioral, inflammatory, and microbial changes in mice consuming different dietary regimes with and without ATIs, consumed ad libitum for eight weeks. We demonstrate that ATIs, with or without a gluten matrix, had an impact on the metabolism and gut microbiota of 5xFAD mice, aggravating pathological hallmarks of AD. If these findings can be translated to patients, an ATI-depleted diet might offer an alternative therapeutic option for AD and warrants clinical intervention studies. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

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14 pages, 6638 KiB

Open AccessArticle

Rapid Alpha-Synuclein Toxicity in a Neural Cell Model and Its Rescue by a Stearoyl-CoA Desaturase Inhibitor

by Elizabeth Terry-Kantor, Arati Tripathi, Thibaut Imberdis, Zachary M. LaVoie, Gary P. H. Ho, Dennis Selkoe, Saranna Fanning, Nagendran Ramalingam and Ulf Dettmer

Int. J. Mol. Sci. 2020, 21(15), 5193; https://doi.org/10.3390/ijms21155193 - 22 Jul 2020

Cited by 21 | Viewed by 3552

Abstract

Genetic and biochemical evidence attributes neuronal loss in Parkinson’s disease (PD) and related brain diseases to dyshomeostasis of the 14 kDa protein α-synuclein (αS). There is no consensus on how αS exerts toxicity. Explanations range from disturbed vesicle biology to proteotoxicity caused by fibrillar aggregates. To probe these mechanisms further, robust cellular toxicity models are needed, but their availability is limited. We previously reported that a shift from dynamic multimers to monomers is an early event in αS dyshomeostasis, as caused by familial PD (fPD)-linked mutants such as E46K. Excess monomers accumulate in round, lipid-rich inclusions. Engineered αS ‘3K’ (E35K+E46K+E61K) amplifies E46K, causing a PD-like, L-DOPA-responsive motor phenotype in transgenic mice. Here, we present a cellular model of αS neurotoxicity after transducing human neuroblastoma cells to express yellow fluorescent protein (YFP)-tagged αS 3K in a doxycycline-dependent manner. αS-3K::YFP induction causes pronounced growth defects that accord with cell death. We tested candidate compounds for their ability to restore growth, and stearoyl-CoA desaturase (SCD) inhibitors emerged as a molecule class with growth-restoring capacity, but the therapeutic window varied among compounds. The SCD inhibitor MF-438 fully restored growth while exerting no apparent cytotoxicity. Our αS bioassay will be useful for elucidating compound mechanisms, for pharmacokinetic studies, and for compound/genetic screens. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

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14 pages, 3202 KiB

Open AccessArticle

Human Neural Stem Cells Encoding ChAT Gene Restore Cognitive Function via Acetylcholine Synthesis, Aβ Elimination, and Neuroregeneration in APPswe/PS1dE9 Mice

by Dongsun Park, Ehn-Kyoung Choi, Tai-Hyoung Cho, Seong Soo Joo and Yun-Bae Kim

Int. J. Mol. Sci. 2020, 21(11), 3958; https://doi.org/10.3390/ijms21113958 - 31 May 2020

Cited by 25 | Viewed by 4698

Abstract

In Alzheimer disease (AD) patients, degeneration of the cholinergic system utilizing acetylcholine for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits without slowing or reversing disease progress, there is a need for effective therapies, and stem cell-based therapeutic approaches targeting AD should fulfill this requirement. We established a human neural stem cell (NSC) line encoding choline acetyltransferase (ChAT) gene, an acetylcholine-synthesizing enzyme. APPswe/PS1dE9 AD model mice transplanted with the F3.ChAT NSCs exhibited improved cognitive function and physical activity. Transplanted F3.ChAT NSCs in the AD mice differentiated into neurons and astrocytes, produced ChAT protein, increased the ACh level, and improved the learning and memory function. F3.ChAT cell transplantation reduced Aβ deposits by recovering microglial function; i.e., the down-regulation of β-secretase and inflammatory cytokines and up-regulation of Aβ-degrading enzyme neprilysin. F3.ChAT cells restored growth factors (GFs) and neurotrophic factors (NFs), and they induced the proliferation of NSCs in the host brain. These findings indicate that NSCs overexpressing ChAT can ameliorate complex cognitive and physical deficits of AD animals by releasing ACh, reducing Aβ deposit, and promoting neuroregeneration by the production of GFs/NFs. It is suggested that NSCs overexpressing ChAT could be a candidate for cell therapy in advanced AD therapy. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

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19 pages, 1948 KiB

Open AccessArticle

Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives

by Paola Rusmini, Riccardo Cristofani, Barbara Tedesco, Veronica Ferrari, Elio Messi, Margherita Piccolella, Elena Casarotto, Marta Chierichetti, Maria Elena Cicardi, Mariarita Galbiati, Cristina Geroni, Paolo Lombardi, Valeria Crippa and Angelo Poletti

Int. J. Mol. Sci. 2020, 21(10), 3443; https://doi.org/10.3390/ijms21103443 - 13 May 2020

Cited by 10 | Viewed by 5552

Abstract

Background: Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the protein quality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy). Mutant proteins that misfold are potentially neurotoxic, thus strategies aimed at preventing their aggregation or at enhancing their clearance are emerging as interesting therapeutic targets for NDs. Methods: We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action. Results: We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. Overlapping effects were observed on other misfolded proteins causative of amyotrophic lateral sclerosis, frontotemporal-lobar degeneration or Huntington disease, but with selective and specific action against each different mutant protein. Conclusions: BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

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Review

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21 pages, 3698 KiB

Open AccessReview

Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity?

by Giada Cipollina, Arash Davari Serej, Gianluca Di Nolfi, Andrea Gazzano, Andrea Marsala, Mauro G. Spatafora and Marco Peviani

Int. J. Mol. Sci. 2020, 21(21), 7923; https://doi.org/10.3390/ijms21217923 - 25 Oct 2020

Cited by 14 | Viewed by 4600

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a complex pathology: (i) the neurodegeneration is chronic and progressive; it starts focally in specific central nervous system (CNS) areas and spreads to different districts; (ii) multiple cell types further than motor neurons (i.e., glial/immune system cells) are actively involved in the disease; (iii) both neurosupportive and neurotoxic neuroinflammatory responses were identified. Microglia cells (a key player of neuroinflammation in the CNS) attracted great interest as potential target cell population that could be modulated to counteract disease progression, at least in preclinical ALS models. However, the heterogeneous/multifaceted microglia cell responses occurring in different CNS districts during the disease represent a hurdle for clinical translation of single-drug therapies. To address this issue, over the past ten years, several studies attempted to dissect the complexity of microglia responses in ALS. In this review, we shall summarize these results highlighting how the heterogeneous signature displayed by ALS microglia reflects not only the extent of neuronal demise in different regions of the CNS, but also variable engagement in the attempts to cope with the neuronal damage. We shall discuss novel avenues opened by the advent of single-cell and spatial transcriptomics technologies, underlining the potential for discovery of novel therapeutic targets, as well as more specific diagnostic/prognostic not-invasive markers of neuroinflammation. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

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13 pages, 1053 KiB

Open AccessReview

Proteostasis and Proteotoxicity in the Network Medicine Era

by Marta Lualdi, Tiziana Alberio and Mauro Fasano

Int. J. Mol. Sci. 2020, 21(17), 6405; https://doi.org/10.3390/ijms21176405 - 3 Sep 2020

Cited by 14 | Viewed by 9387

Abstract

Neurodegenerative proteinopathies are complex diseases that share some pathogenetic processes. One of these is the failure of the proteostasis network (PN), which includes all components involved in the synthesis, folding, and degradation of proteins, thus leading to the aberrant accumulation of toxic protein aggregates in neurons. The single components that belong to the three main modules of the PN are highly interconnected and can be considered as part of a single giant network. Several pharmacological strategies have been proposed to ameliorate neurodegeneration by targeting PN components. Nevertheless, effective disease-modifying therapies are still lacking. In this review article, after a general description of the PN and its failure in proteinopathies, we will focus on the available pharmacological tools to target proteostasis. In this context, we will discuss the main advantages of systems-based pharmacology in contrast to the classical targeted approach, by focusing on network pharmacology as a strategy to innovate rational drug design. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

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25 pages, 401 KiB

Open AccessReview

Proteotoxicity and Neurodegenerative Diseases

by Clara Ruz, Jose Luis Alcantud, Francisco Vives Montero, Raquel Duran and Sara Bandres-Ciga

Int. J. Mol. Sci. 2020, 21(16), 5646; https://doi.org/10.3390/ijms21165646 - 6 Aug 2020

Cited by 40 | Viewed by 3957

Abstract

Neurodegenerative diseases are a major burden for our society, affecting millions of people worldwide. A main goal of past and current research is to enhance our understanding of the mechanisms underlying proteotoxicity, a common theme among these incurable and debilitating conditions. Cell proteome alteration is considered to be one of the main driving forces that triggers neurodegeneration, and unraveling the biological complexity behind the affected molecular pathways constitutes a daunting challenge. This review summarizes the current state on key processes that lead to cellular proteotoxicity in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, providing a comprehensive landscape of recent literature. A foundational understanding of how proteotoxicity affects disease etiology and progression may provide essential insight towards potential targets amenable of therapeutic intervention. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

25 pages, 1968 KiB

Open AccessReview

Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA

by Fiona Limanaqi, Carla Letizia Busceti, Francesca Biagioni, Federica Cantini, Paola Lenzi and Francesco Fornai

Int. J. Mol. Sci. 2020, 21(11), 4021; https://doi.org/10.3390/ijms21114021 - 4 Jun 2020

Cited by 7 | Viewed by 5092

Abstract

The coordinated activities of autophagy and the ubiquitin proteasome system (UPS) are key to preventing the aggregation and toxicity of misfold-prone proteins which manifest in a number of neurodegenerative disorders. These include proteins which are encoded by genes containing nucleotide repeat expansions. In the present review we focus on the overlapping role of autophagy and the UPS in repeat expansion proteotoxicity associated with chromosome 9 open reading frame 72 (C9ORF72) and androgen receptor (AR) genes, which are implicated in two motor neuron disorders, amyotrophic lateral sclerosis (ALS) and spinal-bulbar muscular atrophy (SBMA), respectively. At baseline, both C9ORF72 and AR regulate autophagy, while their aberrantly-expanded isoforms may lead to a failure in both autophagy and the UPS, further promoting protein aggregation and toxicity within motor neurons and skeletal muscles. Besides proteotoxicity, autophagy and UPS alterations are also implicated in neuromuscular junction (NMJ) alterations, which occur early in both ALS and SBMA. In fact, autophagy and the UPS intermingle with endocytic/secretory pathways to regulate axonal homeostasis and neurotransmission by interacting with key proteins which operate at the NMJ, such as agrin, acetylcholine receptors (AChRs), and adrenergic beta2 receptors (B2-ARs). Thus, alterations of autophagy and the UPS configure as a common hallmark in both ALS and SBMA disease progression. The findings here discussed may contribute to disclosing overlapping molecular mechanisms which are associated with a failure in cell-clearing systems in ALS and SBMA. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

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19 pages, 1184 KiB

Open AccessReview

Shared Genomic and Proteomic Contribution of Amyloid and Tau Protein Characteristic of Alzheimer’s Disease to Brain Ischemia

by Ryszard Pluta, Marzena Ułamek-Kozioł, Sławomir Januszewski and Stanisław J. Czuczwar

Int. J. Mol. Sci. 2020, 21(9), 3186; https://doi.org/10.3390/ijms21093186 - 30 Apr 2020

Cited by 14 | Viewed by 3162

Abstract

Post-ischemic brain damage is associated with the deposition of folding proteins such as the amyloid and tau protein in the intra- and extracellular spaces of brain tissue. In this review, we summarize the protein changes associated with Alzheimer’s disease and their gene expression (amyloid protein precursor and tau protein) after ischemia-reperfusion brain injury and their role in the post-ischemic injury. Recent advances in understanding the post-ischemic neuropathology have revealed dysregulation of amyloid protein precursor, α-secretase, β-secretase, presenilin 1 and 2, and tau protein genes after ischemic brain injury. However, reduced expression of the α-secretase in post-ischemic brain causes neurons to be less resistant to injury. In this review, we present the latest evidence that proteins associated with Alzheimer’s disease and their genes play a key role in progressive brain damage due to ischemia and reperfusion, and that an ischemic episode is an essential and leading supplier of proteins and genes associated with Alzheimer’s disease in post-ischemic brain. Understanding the underlying processes of linking Alzheimer’s disease-related proteins and their genes in post-ischemic brain injury with the risk of developing Alzheimer’s disease will provide the most significant goals for therapeutic development to date. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

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31 pages, 1294 KiB

Open AccessReview

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

by Fiona Limanaqi, Francesca Biagioni, Stefano Gambardella, Pietro Familiari, Alessandro Frati and Francesco Fornai

Int. J. Mol. Sci. 2020, 21(8), 3028; https://doi.org/10.3390/ijms21083028 - 24 Apr 2020

Cited by 54 | Viewed by 7800

Abstract

Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies. Full article

(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)

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