scholarly journals Misfolded proteins share a common capacity in disrupting LLPS organizing membrane-less organelles

2018 ◽  
Author(s):  
Jian Kang ◽  
Liangzhong Lim ◽  
Jianxing Song
Keyword(s):  
Nmr Spectroscopy ◽  
Neurodegenerative Diseases ◽  
Underlying Mechanism ◽  
Misfolded Proteins ◽  
Liquid Droplets ◽  
Differential Capacity ◽  
Hydrodynamic Properties ◽  
Great Cost ◽  
Unfolded State ◽  
Dynamic Droplets

AbstractProfilin-1 mutants cause ALS by gain of toxicity but the underlying mechanism remains unknown. Here we showed that three PFN1 mutants have differential capacity in disrupting dynamics of FUS liquid droplets underlying the formation of stress granules (SGs). Subsequently we extensively characterized conformations, dynamics and hydrodynamic properties of C71G-PFN1, FUS droplets and their interaction by NMR spectroscopy. C71G-PFN1 co-exists between the folded (55.2%) and unfolded (44.8%) states undergoing exchanges at 11.7 Hz, while its unfolded state non-specifically interacts with FUS droplets. Results together lead to a model for dynamic droplets to recruit misfolded proteins, which functions seemingly at great cost: simple accumulation of misfolded proteins within liquid droplets is sufficient to reduce their dynamics. Further aggregation of misfolded proteins within droplets might irreversibly disrupt/destroy structures and dynamics of droplets, as increasingly observed on SGs, an emerging target for various neurodegenerative diseases. Therefore, our study implies that other misfolded proteins might also share the capacity in disrupting LLPS.

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 Anti–Na+/K+-ATPase immunotherapy ameliorates α-synuclein pathology through activation of Na+/K+-ATPase α1–dependent autophagy

2021 ◽  
Vol 7 (5) ◽  
pp. eabc5062
Author(s):  
Lei Cao ◽  
Siping Xiong ◽  
Zhiyuan Wu ◽  
Lei Ding ◽  
Yebo Zhou ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tyrosine Hydroxylase ◽  
Neurodegenerative Diseases ◽  
Motor Function ◽  
Therapeutic Strategy ◽  
Underlying Mechanism ◽  
Behavioral Tests ◽  
Behavioral Deficits ◽  
Cellular Homeostasis ◽  
Beneficial Effects

Na+/K+-ATPase (NKA) plays important roles in maintaining cellular homeostasis. Conversely, reduced NKA activity has been reported in aging and neurodegenerative diseases. However, little is known about the function of NKA in the pathogenesis of Parkinson’s disease (PD). Here, we report that reduction of NKA activity in NKAα1+/− mice aggravates α-synuclein–induced pathology, including a reduction in tyrosine hydroxylase (TH) and deficits in behavioral tests for memory, learning, and motor function. To reverse this effect, we generated an NKA-stabilizing monoclonal antibody, DR5-12D, against the DR region (897DVEDSYGQQWTYEQR911) of the NKAα1 subunit. We demonstrate that DR5-12D can ameliorate α-synuclein–induced TH loss and behavioral deficits by accelerating α-synuclein degradation in neurons. The underlying mechanism for the beneficial effects of DR5-12D involves activation of NKAα1-dependent autophagy via increased AMPK/mTOR/ULK1 pathway signaling. Cumulatively, this work demonstrates that NKA activity is neuroprotective and that pharmacological activation of this pathway represents a new therapeutic strategy for PD.

scholarly journals Amitriptyline interferes with autophagy-mediated clearance of protein aggregates via inhibiting autophagosome maturation in neuronal cells

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Yoonjung Kwon ◽  
Yeojin Bang ◽  
Soung-Hee Moon ◽  
Aeri Kim ◽  
Hyun Jin Choi
Keyword(s):  
Neurodegenerative Diseases ◽  
Depressive Disorders ◽  
Neuronal Cells ◽  
Protein Aggregates ◽  
Underlying Mechanism ◽  
Tricyclic Antidepressant ◽  
Autophagic Flux ◽  
Autophagosome Maturation

Abstract Amitriptyline is a tricyclic antidepressant commonly prescribed for major depressive disorders, as well as depressive symptoms associated with various neurological disorders. A possible correlation between the use of tricyclic antidepressants and the occurrence of Parkinson’s disease has been reported, but its underlying mechanism remains unknown. The accumulation of misfolded protein aggregates has been suggested to cause cellular toxicity and has been implicated in the common pathogenesis of neurodegenerative diseases. Here, we examined the effect of amitriptyline on protein clearance and its relevant mechanisms in neuronal cells. Amitriptyline exacerbated the accumulation of abnormal aggregates in both in vitro neuronal cells and in vivo mice brain by interfering with the (1) formation of aggresome-like aggregates and (2) autophagy-mediated clearance of aggregates. Amitriptyline upregulated LC3B-II, but LC3B-II levels did not increase further in the presence of NH4Cl, which suggests that amitriptyline inhibited autophagic flux rather than autophagy induction. Amitriptyline interfered with the fusion of autophagosome and lysosome through the activation of PI3K/Akt/mTOR pathway and Beclin 1 acetylation, and regulated lysosome positioning by increasing the interaction between proteins Arl8, SKIP, and kinesin. To the best of our knowledge, we are the first to demonstrate that amitriptyline interferes with autophagic flux by regulating the autophagosome maturation during autophagy in neuronal cells. The present study could provide neurobiological clue for the possible correlation between the amitriptyline use and the risk of developing neurodegenerative diseases.

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 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.

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