scholarly journals Targeting Misfolded Proteins to Fight Neurodegenerative Diseases

PLoS Biology ◽  
2010 ◽  
Vol 8 (1) ◽  
pp. e1000290 ◽  
Author(s):  
Kira Heller
Keyword(s):  
Neurodegenerative Diseases ◽  
Misfolded Proteins

scholarly journals Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 207
Author(s):  
Diane L. Ritchie ◽  
Marcelo A. Barria
Keyword(s):  
Public Health ◽  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Experimental Models ◽  
Misfolded Proteins ◽  
Current Evidence

The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.

scholarly journals Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases

2017 ◽  
Vol 216 (12) ◽  
pp. 3917-3929 ◽  
Author(s):  
Hibiki Kawamata ◽  
Giovanni Manfredi
Keyword(s):  
Nervous System ◽  
Oxidative Phosphorylation ◽  
Neurodegenerative Diseases ◽  
Gene Mutations ◽  
Misfolded Proteins ◽  
Protein Homeostasis ◽  
Abnormal Protein ◽  
Oxidative Phosphorylation System ◽  
Intermediate Metabolism

Mitochondria participate in essential processes in the nervous system such as energy and intermediate metabolism, calcium homeostasis, and apoptosis. Major neurodegenerative diseases are characterized pathologically by accumulation of misfolded proteins as a result of gene mutations or abnormal protein homeostasis. Misfolded proteins associate with mitochondria, forming oligomeric and fibrillary aggregates. As mitochondrial dysfunction, particularly of the oxidative phosphorylation system (OXPHOS), occurs in neurodegeneration, it is postulated that such defects are caused by the accumulation of misfolded proteins. However, this hypothesis and the pathological role of proteinopathies in mitochondria remain elusive. In this study, we critically review the proposed mechanisms whereby exemplary misfolded proteins associate with mitochondria and their consequences on OXPHOS.

scholarly journals Genealogy of the neurodegenerative diseases based on a meta-analysis of age-stratified incidence data

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniela Gerovska ◽  
Haritz Irizar ◽  
David Otaegi ◽  
Isidre Ferrer ◽  
Adolfo López de Munain ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Meta Analysis ◽  
Disease Onset ◽  
Epidemiological Studies ◽  
Misfolded Proteins ◽  
Mathematical Framework ◽  
Dynamic Adjustment ◽  
Genealogical Tree ◽  
Incidence Data ◽  
Multistep Model

Abstract While the central common feature of the neurodegenerative diseases (NDs) is the accumulation of misfolded proteins, they share other pathogenic mechanisms. However, we miss an explanation for the onset of the NDs. The mechanisms through which genetic mutations, present from conception are expressed only after several decades of life are unknown. We aim to find clues on the complexity of the disease onset trigger of the different NDs expressed in the number of steps of factors related to a disease. We collected brain autopsies on diseased patients with NDs, and found a dynamic increase of the ND multimorbidity with the advance of age. Together with the observation that the NDs accumulate multiple misfolded proteins, and the same misfolded proteins are involved in more than one ND, motivated us to propose a model for a genealogical tree of the NDs. To collect the dynamic data needed to build the tree, we used a Big-data approach that searched automatically epidemiological datasets for age-stratified incidence of NDs. Based on meta-analysis of over 400 datasets, we developed an algorithm that checks whether a ND follows a multistep model, finds the number of steps necessary for the onset of each ND, finds the number of common steps with other NDs and the number of specific steps of each ND, and builds with these findings a parsimony tree of the genealogy of the NDs. The tree discloses three types of NDs: the stem NDs with less than 3 steps; the trunk NDs with 5 to 6 steps; and the crown NDs with more than 7 steps. The tree provides a comprehensive understanding of the relationship across the different NDs, as well as a mathematical framework for dynamic adjustment of the genealogical tree of the NDs with the appearance of new epidemiological studies and the addition of new NDs to the model, thus setting the basis for the search for the identity and order of these steps. Understanding the complexity, or number of steps, of factors related to disease onset trigger is important prior deciding to study single factors for a multiple steps disease.

scholarly journals Transcellular spreading of huntingtin aggregates in the Drosophila brain

2015 ◽  
Vol 112 (39) ◽  
pp. E5427-E5433 ◽  
Author(s):  
Daniel T. Babcock ◽  
Barry Ganetzky
Keyword(s):  
Fusion Protein ◽  
Neurodegenerative Diseases ◽  
Disease Progression ◽  
Protein Aggregates ◽  
Misfolded Proteins ◽  
Drosophila Brain ◽  
Active Release ◽  
Fluorescent Tag ◽  
The Brain ◽  
Expanded Form

A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamine-expanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington’s disease. Upon expression of this construct in a defined subset of neurons, we demonstrate that protein aggregates accumulate at synaptic terminals and progressively spread throughout the brain. These aggregates are internalized and accumulate within other neurons. We show that Htt aggregates cause non–cell-autonomous pathology, including loss of vulnerable neurons that can be prevented by inhibiting endocytosis in these neurons. Finally we show that the release of aggregates requires N-ethylmalemide–sensitive fusion protein 1, demonstrating that active release and uptake of Htt aggregates are important elements of spreading and disease progression.

scholarly journals Differential HspBP1 expression accounts for the greater vulnerability of neurons than astrocytes to misfolded proteins

2017 ◽  
Vol 114 (37) ◽  
pp. E7803-E7811 ◽  
Author(s):  
Ting Zhao ◽  
Yan Hong ◽  
Peng Yin ◽  
Shihua Li ◽  
Xiao-Jiang Li
Keyword(s):  
Neurodegenerative Diseases ◽  
Critical Role ◽  
Misfolded Proteins ◽  
Inhibitory Protein ◽  
Interacting Protein ◽  
C Terminus ◽  
Differential Vulnerability ◽  
Disease Protein ◽  
Knockin Mouse

Although it is well known that astrocytes are less vulnerable than neurons in neurodegenerative diseases, the mechanism behind this differential vulnerability is unclear. Here we report that neurons and astrocytes show markedly different activities in C terminus of Hsp70-interacting protein (CHIP), a cochaperone of Hsp70. In astrocytes, CHIP is more actively monoubiquitinated and binds to mutant huntingtin (mHtt), the Huntington’s disease protein, more avidly, facilitating its K48-linked polyubiquitination and degradation. Astrocytes also show the higher level and heat-shock induction of Hsp70 and faster CHIP-mediated degradation of various misfolded proteins than neurons. In contrast to astrocytes, neurons express abundant HspBP1, a CHIP inhibitory protein, resulting in the low activity of CHIP. Silencing HspBP1 expression via CRISPR-Cas9 in neurons ameliorated mHtt aggregation and neuropathology in HD knockin mouse brains. Our findings indicate a critical role of HspBP1 in differential CHIP/Hsp70 activities in neuronal and glial cells and the greater neuronal vulnerability to misfolded proteins in neurodegenerative diseases.

scholarly journals Astrocytes in Neurodegenerative Diseases: A Perspective from Tauopathy and α-Synucleinopathy

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 938
Author(s):  
Peng Wang ◽  
Yihong Ye
Keyword(s):  
Neurodegenerative Diseases ◽  
Inclusion Bodies ◽  
Physiological State ◽  
Neuronal Cell ◽  
Misfolded Proteins ◽  
Donor Cells ◽  
Highly Sensitive ◽  
Parkinson’S Diseases ◽  
Inflammatory State ◽  
Neuronal Functions

Neurodegenerative diseases are aging-associated chronic pathological conditions affecting primarily neurons in humans. Inclusion bodies containing misfolded proteins have emerged as a common pathologic feature for these diseases. In many cases, misfolded proteins produced by a neuron can be transmitted to another neuron or a non-neuronal cell, leading to the propagation of disease-associated pathology. While undergoing intercellular transmission, misfolded proteins released from donor cells can often change the physiological state of recipient cells. Accumulating evidence suggests that astrocytes are highly sensitive to neuron-originated proteotoxic insults, which convert them into an active inflammatory state. Conversely, activated astrocytes can release a plethora of factors to impact neuronal functions. This review summarizes our current understanding of the complex molecular interplays between astrocyte and neuron, emphasizing on Tau and α-synuclein (α-syn), the disease-driving proteins for Alzheimer’s and Parkinson’s diseases, respectively.

scholarly journals G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Tao Zhang ◽  
Kangyun Dong ◽  
Wei Liang ◽  
Daichao Xu ◽  
Hongguang Xia ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodegenerative Diseases ◽  
G Protein ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
G Protein Coupled Receptors ◽  
Misfolded Proteins ◽  
Ubiquitin Ligase Complex ◽  
Wide Range ◽  
G Protein Coupled

Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian ortholog of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. In this study, we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of G-protein-coupled receptor (GPCR) ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington's disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases.

Neurodegenerative Diseases as Protein Misfolding Disorders

2016 ◽  
Author(s):  
Tomohiro Nakamura ◽  
Stuart A. Lipton
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein S ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Redox Stress ◽  
Chemical Mechanisms ◽  
Ubiquitin Proteasome

Neurodegenerative diseases (NDDs) often represent disorders of protein folding. Rather than large aggregates, recent evidence suggests that soluble oligomers of misfolded proteins are the most neurotoxic species. Emerging evidence points to small, soluble oligomers of misfolded proteins as the cause of synaptic dysfunction and loss, the major pathological correlate to disease progression in many NDDs including Alzheimer’s disease. The protein quality control machinery of the cell, which includes molecular chaperones as found in the endoplasmic reticulum (ER), the ubiquitin-proteasome system (UPS), and various forms of autophagy, can counterbalance the accumulation of misfolded proteins to some extent. Their ability to eliminate the neurotoxic effects of misfolded proteins, however, declines with age. A plausible explanation for the age-dependent deterioration of the quality control machinery involves compromise of these systems by excessive generation of reactive oxygen species (ROS), such as superoxide anion (O2-), and reactive nitrogen species (RNS), such as nitric oxide (NO). The resulting redox stress contributes to the accumulation of misfolded proteins. Here, we focus on aberrantly increased generation of NO-related species since this process appears to accelerate the manifestation of key neuropathological features, including protein misfolding. We review the chemical mechanisms of posttranslational modification by RNS such as protein S-nitrosylation of critical cysteine thiol groups and nitration of tyrosine residues, showing how they contribute to the pathogenesis of NDDs.

Sign in / Sign up

Export Citation Format

Share Document