Do Post-Translational Modifications Influence Protein Aggregation in Neurodegenerative Diseases: A Systematic Review

The accumulation of abnormal protein aggregates represents a universal hallmark of neurodegenerative diseases (NDDs). Post-translational modifications (PTMs) regulate protein structure and function. Dysregulated PTMs may influence the propensity for protein aggregation in NDD-proteinopathies. To investigate this, we systematically reviewed the literature to evaluate effects of PTMs on aggregation propensity for major proteins linked to the pathogenesis and/or progression of NDDs. A search of PubMed, MEDLINE, EMBASE, and Web of Science Core Collection was conducted to retrieve studies that investigated an association between PTMs and protein aggregation in seven NDDs: Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxias, transmissible spongiform encephalopathy, and multiple sclerosis. Together, 1222 studies were identified, of which 69 met eligibility criteria. We identified that the following PTMs, in isolation or combination, potentially act as modulators of proteinopathy in NDDs: isoaspartate formation in Aβ, phosphorylation of Aβ or tau in AD; acetylation, 4-hydroxy-2-neonal modification, O-GlcNAcylation or phosphorylation of α-synuclein in PD; acetylation or phosphorylation of TAR DNA-binding protein-43 in ALS, and SUMOylation of superoxide dismutase-1 in ALS; and phosphorylation of huntingtin in HD. The potential pharmacological manipulation of these aggregation-modulating PTMs represents an as-yet untapped source of therapy to treat NDDs.

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Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽

10.3390/biology10020163 ◽

2021 ◽

Vol 10 (2) ◽

pp. 163

Author(s):

Swapnil Gupta ◽

Panpan You ◽

Tanima SenGupta ◽

Hilde Nilsen ◽

Kulbhushan Sharma

Keyword(s):

Dna Repair ◽

Neurodegenerative Diseases ◽

3D Models ◽

Model Systems ◽

Spinocerebellar Ataxias ◽

C Elegans ◽

Cellular Processes ◽

Age Related ◽

Damage Response ◽

Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

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The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab029 ◽

2021 ◽

Author(s):

Benjamin C Creekmore ◽

Yi-Wei Chang ◽

Edward B Lee

Keyword(s):

Neurodegenerative Diseases ◽

Protein Aggregation ◽

Neurodegenerative Disease ◽

Electron Tomography ◽

Ubiquitin Proteasome System ◽

26S Proteasome ◽

X Ray Crystallography ◽

New Information ◽

A Cell ◽

Regulate Protein

Abstract Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.

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Astroglial Connexins in Neurodegenerative Diseases

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.657514 ◽

2021 ◽

Vol 14 ◽

Author(s):

Xiaomin Huang ◽

Yixun Su ◽

Nan Wang ◽

Hui Li ◽

Zhigang Li ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Neuronal Function ◽

Gap Junction Channels ◽

Normal Functions ◽

Functional Remodeling ◽

The Central Nervous System ◽

Key Aspects ◽

And Function ◽

Lateral Sclerosis

Astrocytes play a crucial role in the maintenance of the normal functions of the Central Nervous System (CNS). During the pathogenesis of neurodegenerative diseases, astrocytes undergo morphological and functional remodeling, a process called reactive astrogliosis, in response to the insults to the CNS. One of the key aspects of the reactive astrocytes is the change in the expression and function of connexins. Connexins are channel proteins that highly expressed in astrocytes, forming gap junction channels and hemichannels, allowing diffusional trafficking of small molecules. Alterations of astrocytic connexin expression and function found in neurodegenerative diseases have been shown to affect the disease progression by changing neuronal function and survival. In this review, we will summarize the role of astroglial connexins in neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Also, we will discuss why targeting connexins can be a plausible therapeutic strategy to manage these neurodegenerative diseases.

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Calcium Hypothesis of Neurodegeneration

10.1093/med/9780190233563.003.0003 ◽

2016 ◽

Author(s):

Daniel A. Ryskamp ◽

Elena Popugaeva ◽

Ilya Bezprozvanny

Keyword(s):

Calcium Homeostasis ◽

Treatment Strategies ◽

Specific Treatment ◽

Monogenic Disease ◽

Pathological Feature ◽

Spinocerebellar Ataxias ◽

Neuronal Circuitry ◽

And Function ◽

Neuronal Physiology ◽

Lateral Sclerosis

Aged-related changes in neuronal physiology and stressors related to specific neurodegenerative diseases collude to undermine neuronal calcium homeostasis, which is a common pathological feature in the initiation and progression of Alzheimer’s disease(AD), Huntington’s disease (HD), Parkinson’s disease, amyotrophic lateral sclerosis, spinocerebellar ataxias, glaucoma, and several other neurodegenerative disorders. Mechanisms of calcium mishandling in these diseases are discussed in this chapter by focusing on HD as an example of a monogenic disease and AD as a multifactorial disease. As aberrant Ca2+ signals are particularly toxic to synaptic elements, this chapter further focuses on issues relevant to development of therapeutics that maintain neuronal circuitry and function through the stabilization of Ca2+ regulation. Ultimately, therapies that promote calcium homeostasis will likely be most effective when used in combination with disease-specific treatment strategies such as elimination of toxic Aβ‎ in AD or polyglutamine expanded Huntingtin protein in HD.

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Antisense oligonucleotides

Neurology Genetics ◽

10.1212/nxg.0000000000000323 ◽

2019 ◽

Vol 5 (2) ◽

pp. e323 ◽

Cited By ~ 34

Author(s):

Daniel R. Scoles ◽

Eric V. Minikel ◽

Stefan M. Pulst

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Antisense Oligonucleotide ◽

Antisense Oligonucleotides ◽

Muscular Atrophy ◽

Target Sequence ◽

Spinocerebellar Ataxias ◽

Complementary Oligonucleotide ◽

Disease Modifying ◽

Lateral Sclerosis

There are few disease-modifying therapeutics for neurodegenerative diseases, but successes on the development of antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy and Duchenne muscular dystrophy predict a robust future for ASOs in medicine. Indeed, existing pipelines for the development of ASO therapies for spinocerebellar ataxias, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, and others, and increased focus by the pharmaceutical industry on ASO development, strengthen the outlook for using ASOs for neurodegenerative diseases. Perhaps the most significant advantage to ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of putative complementary oligonucleotide therapeutics. In this review, we describe the various types of ASOs, how they are used therapeutically, and the present efforts to develop new ASO therapies that will contribute to a forthcoming toolkit for treating multiple neurodegenerative diseases.

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Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

Quarterly Reviews of Biophysics ◽

10.1017/s0033583506004422 ◽

2006 ◽

Vol 39 (2) ◽

pp. 167-201 ◽

Cited By ~ 281

Author(s):

Hilal A. Lashuel ◽

Peter T. Lansbury

Keyword(s):

Neurodegenerative Diseases ◽

Protein Aggregation ◽

Amyloid Fibril ◽

Amyloid Β ◽

Fibril Formation ◽

Common Mechanism ◽

Spongiform Encephalopathy ◽

Amyloid Fibril Formation ◽

Amyloid Diseases

1. Introduction 22. What is the significance of the shared structural properties of disease-associated protein fibrils? 32.1 Mechanism of amyloid fibril formation in vitro 62.1.1 In vitro fibril formation involves transient population of ordered aggregates of intermediate stability, or protofibrils 63. Toxic properties of protofibrils 73.1 Protofibrils, rather than fibrils, are likely to be pathogenic 73.2 The toxic protofibril may be a mixture of related species 83.3 Morphological similarities of protofibrils suggest a common mechanism of toxicity 93.4 Are the amyloid diseases a subset of a much larger class of previously unrecognized protofibril diseases? 93.5 Fibrils, in the form of aggresomes, may function to sequester toxic protofibrils 94. Amyloid pores, a common structural link among protein aggregation neurodegenerative diseases 104.1 Mechanistic studies of amyloid fibril formation reveal common features, including pore-like protofibrils 104.1.1 Amyloid-β (Aβ) (Alzheimer's disease) 104.1.2 α-Synuclein (PD and diffuse Lewy body disease) 124.1.3 ABri (familial British dementia) 134.1.4 Superoxide dismutase-1 (amyotrophic lateral sclerosis) 134.1.5 Prion protein (Creutzfeldt–Jakob disease, bovine spongiform encephalopathy, etc.) 144.1.6 Huntingtin (Huntington's disease) 144.2 Amyloidogenic proteins that are not linked to disease also from pore-like protofibrils 154.3 Amyloid proteins form non-fibrillar aggregates that have properties of protein channels or pores 154.3.1 Aβ ‘channels’ 154.3.2 α-Synuclein ‘pores’ 164.3.3 PrP ‘channels’ 164.3.4 Polyglutamine ‘channels’ 174.4 Nature uses β-strand-mediated protein oligomerization to construct pore-forming toxins 175. Mechanisms of protofibril induced toxicity in protein aggregation diseases 195.1 The amyloid pore can explain the age-association and cell-type selectivity of the neurodegenerative diseases 195.2 Protofibrils may promote their own accumulation by inhibiting the proteasome 206. Testing the amyloid pore hypothesis by attempting to disprove it 217. Acknowledgments 228. References 22Protein fibrillization is implicated in the pathogenesis of most, if not all, age-associated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ‘amyloid pore’. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.

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The Antiaggregative and Antiamyloidogenic Properties of Nanoparticles: A Promising Tool for the Treatment and Diagnostics of Neurodegenerative Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3534570 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Monika Pichla ◽

Grzegorz Bartosz ◽

Izabela Sadowska-Bartosz

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Protein Aggregation ◽

High Throughput ◽

Diagnostic Tool ◽

Neurodegenerative Disorders ◽

High Throughput Screening ◽

Promising Tool ◽

Socioeconomic Burden ◽

Lateral Sclerosis

Due to the progressive aging of the society, the prevalence and socioeconomic burden of neurodegenerative diseases are predicted to rise. The most common neurodegenerative disorders nowadays, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, can be classified as proteinopathies. They can be either synucleinopathies, amyloidopathies, tauopathies, or TDP-43-related proteinopathies; thus, nanoparticles with a potential ability to inhibit pathological protein aggregation and/or degrade already existing aggregates can be a promising approach in the treatment of neurodegenerative diseases. As it turns out, nanoparticles can be a double-edged sword; they can either promote or inhibit protein aggregation, depending on coating, shape, size, surface charge, and concentration. In this review, we aim to emphasize the need of a breakthrough in the treatment of neurodegenerative disorders and draw attention to nanomaterials, as they can also serve as a diagnostic tool for protein aggregates or can be used in a high-throughput screening for novel antiaggregative compounds.

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Defining the Protein Seeds of Neurodegeneration using Real-Time Quaking-Induced Conversion Assays

Biomolecules ◽

10.3390/biom10091233 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1233

Author(s):

Matteo Manca ◽

Allison Kraus

Keyword(s):

Neurodegenerative Diseases ◽

Real Time ◽

Chronic Traumatic Encephalopathy ◽

Prion Diseases ◽

Transmissible Spongiform Encephalopathy ◽

Lewy Bodies ◽

Misfolded Proteins ◽

Spongiform Encephalopathy ◽

Diagnostic Assays ◽

Seed Distribution

Neurodegenerative diseases are characterized by the accumulation of disease-related misfolded proteins. It is now widely understood that the characteristic self-amplifying (i.e., seeding) capacity once only attributed to the prions of transmissible spongiform encephalopathy diseases is a feature of other misfolded proteins of neurodegenerative diseases, including tau, Aβ, and αSynuclein (αSyn). Ultrasensitive diagnostic assays, known as real-time quaking-induced conversion (RT-QuIC) assays, exploit these seeding capabilities in order to exponentially amplify protein seeds from various biospecimens. To date, RT-QuIC assays have been developed for the detection of protein seeds related to known prion diseases of mammals, the αSyn aggregates of Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, and the tau aggregates of Alzheimer’s disease, chronic traumatic encephalopathy, and other tauopathies including progressive supranuclear palsy. Application of these assays to premortem human biospecimens shows promise for diagnosis of neurodegenerative disease and is an area of active investigation. RT-QuIC assays are also powerful experimental tools that can be used to dissect seeding networks within and between tissues and to evaluate how protein seed distribution and quantity correlate to disease-related outcomes in a host. As well, RT-QuIC application may help characterize molecular pathways influencing protein seed accumulation, transmission, and clearance. In this review we discuss the application of RT-QuIC assays as diagnostic, experimental, and structural tools for detection and discrimination of PrP prions, tau, and αSyn protein seeds.

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Mitochondrial Transport and Turnover in the Pathogenesis of Amyotrophic Lateral Sclerosis

Biology ◽

10.3390/biology8020036 ◽

2019 ◽

Vol 8 (2) ◽

pp. 36 ◽

Cited By ~ 8

Author(s):

Veronica Granatiero ◽

Giovanni Manfredi

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Motor Neurons ◽

Ionic Currents ◽

High Energy ◽

Mitochondrial Transport ◽

Mitochondrial Functions ◽

Energy Consuming ◽

And Function ◽

Lateral Sclerosis

Neurons are high-energy consuming cells, heavily dependent on mitochondria for ATP generation and calcium buffering. These mitochondrial functions are particularly critical at specific cellular sites, where ionic currents impose a large energetic burden, such as at synapses. The highly polarized nature of neurons, with extremely large axoplasm relative to the cell body, requires mitochondria to be efficiently transported along microtubules to reach distant sites. Furthermore, neurons are post-mitotic cells that need to maintain pools of healthy mitochondria throughout their lifespan. Hence, mitochondrial transport and turnover are essential processes for neuronal survival and function. In neurodegenerative diseases, the maintenance of a healthy mitochondrial network is often compromised. Numerous lines of evidence indicate that mitochondrial impairment contributes to neuronal demise in a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), where degeneration of motor neurons causes a fatal muscle paralysis. Dysfunctional mitochondria accumulate in motor neurons affected by genetic or sporadic forms of ALS, strongly suggesting that the inability to maintain a healthy pool of mitochondria plays a pathophysiological role in the disease. This article critically reviews current hypotheses on mitochondrial involvement in the pathogenesis of ALS, focusing on the alterations of mitochondrial axonal transport and turnover in motor neurons.

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Methylene blue inhibits nucleation and elongation of SOD1 amyloid fibrils

PeerJ ◽

10.7717/peerj.9719 ◽

2020 ◽

Vol 8 ◽

pp. e9719

Author(s):

Greta Musteikyte ◽

Mantas Ziaunys ◽

Vytautas Smirnovas

Keyword(s):

Methylene Blue ◽

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

Neurodegenerative Diseases ◽

Protein Aggregation ◽

Amyloid Fibrils ◽

Late Onset ◽

Amyloid Aggregation ◽

Amyloidogenic Proteins ◽

Lateral Sclerosis

Protein aggregation into highly-structured amyloid fibrils is linked to several neurodegenerative diseases. Such fibril formation by superoxide dismutase I (SOD1) is considered to be related to amyotrophic lateral sclerosis, a late-onset and fatal disorder. Despite much effort and the discovery of numerous anti-amyloid compounds, no effective cure or treatment is currently available. Methylene blue (MB), a phenothiazine dye, has been shown to modulate the aggregation of multiple amyloidogenic proteins. In this work we show its ability to inhibit both the spontaneous amyloid aggregation of SOD1 as well as elongation of preformed fibrils.

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