scholarly journals Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States?

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 289
Author(s):  
Emelie E. Aspholm ◽  
Irena Matečko-Burmann ◽  
Björn M. Burmann
Keyword(s):  
Molecular Chaperones ◽  
Mitochondrial Membrane ◽  
Structural Transition ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Protein Aggregates ◽  
Active Role ◽  
Proteolytic Processing ◽  
Membrane Disruption

The property of molecular chaperones to dissolve protein aggregates of Parkinson-related α-synuclein has been known for some time. Recent findings point to an even more active role of molecular chaperones preventing the transformation of α-synuclein into pathological states subsequently leading to the formation of Lewy bodies, intracellular inclusions containing protein aggregates as well as broken organelles found in the brains of Parkinson’s patients. In parallel, a short motif around Tyr39 was identified as being crucial for the aggregation of α-synuclein. Interestingly, this region is also one of the main segments in contact with a diverse pool of molecular chaperones. Further, it could be shown that the inhibition of the chaperone:α-synuclein interaction leads to a binding of α-synuclein to mitochondria, which could also be shown to lead to mitochondrial membrane disruption as well as the possible proteolytic processing of α-synuclein by mitochondrial proteases. Here, we will review the current knowledge on the role of molecular chaperones in the regulation of physiological functions as well as the direct consequences of impairing these interactions—i.e., leading to enhanced mitochondrial interaction and consequential mitochondrial breakage, which might mark the initial stages of the structural transition of α-synuclein towards its pathological states.

scholarly journals Neurons and Glia Interplay in α-Synucleinopathies

2021 ◽  
Vol 22 (9) ◽  
pp. 4994
Author(s):  
Panagiota Mavroeidi ◽  
Maria Xilouri
Keyword(s):  
Glial Cells ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Glial Function ◽  
Presynaptic Protein

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

scholarly journals The Fourth IOCDC

CNS Spectrums ◽  
2000 ◽  
Vol 5 (S4) ◽  
pp. 4-4
Author(s):  
Eric Hollander ◽  
Joseph Zohar ◽  
Donatella Marazziti
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Brain Stimulation ◽  
Current Knowledge ◽  
Active Role ◽  
Cortical Inhibition ◽  
Obsessive Compulsive ◽  
Future Directions ◽  
Compulsive Disorder ◽  
Ablative Surgery

The Fourth International Obsessive Compulsive Disorder Conference (IOCDC) was held February 10–12, 2000, on the beautiful island of St. Thomas. The IOCDC is an annual meeting which brings together the world's leading experts in obsessive-compulsive disorder (OCD) and related disorders in a small workshop setting to present recent research advances, discuss gaps in our current knowledge, and plan or international approaches that address these knowledge gaps. The IOCDC meetings have been held on islands on both sides of the Atlantic—Capri, Guadeloupe, Madeira, and now St. Thomas.The International Organizing Committee consists of Eric Hollander, MD (USA), Joseph Zohar, MD (Israel), and Donatella Marazziti, MD (Italy). The proceedings are generously supported by an unrestricted educational grant from Solvay Pharmaceuticals Inc. and Solvay Pharmaceuticals, and we would like to acknowledge the very important contributions of Chantal Vekens and Mary Blangiardo of Solvay. Also, an mportant part of the success of these meetings stems from the very active role of the chairpersons and cochairpersons of the workshops who lead the discussions, who synthesize the future directions and prepare the manuscripts that result from these discussions that appear in this academic supplement.The meeting led off with a state-of-the-art plenary address by Mark George, MD (USA), describing how new methods of brain stimulation are improving research and therapy in OCD and promise to revolutionize neuropsychiatric research and herapy over the next decade. He describes how transcranial magnetic stimulation (TMS) is used to test the circuits in OCD and test electrophysiologic evaluations of cortical inhibition n OCD. Newer techniques that are less invasive than ablative surgery and appear promising in OCD therapy include vagus nerve stimulation and deep brain stimulation.

The active role of Ca2+ ions in Aβ-mediated membrane damage

2018 ◽  
Vol 54 (29) ◽  
pp. 3629-3631 ◽  
Author(s):  
Michele F. M. Sciacca ◽  
Irene Monaco ◽  
Carmelo La Rosa ◽  
Danilo Milardi
Keyword(s):  
Calcium Ions ◽  
Membrane Damage ◽  
Active Role ◽  
Membrane Disruption ◽  
Induced Membrane ◽  
Membrane Poration

Calcium ions inhibits Aβ induced membrane poration by small-sized oligomers but significantly foster fiber-dependent membrane disruption.

scholarly journals The role of pro-domains in human growth factors and cytokines

2021 ◽  
Author(s):  
Matthew Ratcliff ◽  
Richard Xu Zhou ◽  
Lutz Jermutus ◽  
Marko Hyvönen
Keyword(s):  
Growth Factors ◽  
Therapeutic Potential ◽  
Human Growth ◽  
Active Role ◽  
Proteolytic Processing ◽  
Protein Families ◽  
Protein Localisation ◽  
Precise Role ◽  
Bioactive Ligand

Many growth factors and cytokines are produced as larger precursors, containing pro-domains, that require proteolytic processing to release the bioactive ligand. These pro-domains can be significantly larger than the mature domains and can play an active role in the regulation of the ligands. Mining the UniProt database, we identified almost one hundred human growth factors and cytokines with pro-domains. These are spread across several unrelated protein families and vary in both their size and composition. The precise role of each pro-domain varies significantly between the protein families. Typically they are critical for controlling bioactivity and protein localisation, and they facilitate diverse mechanisms of activation. Significant gaps in our understanding remain for pro-domain function — particularly their fate once the bioactive ligand has been released. Here we provide an overview of pro-domain roles in human growth factors and cytokines, their processing, regulation and activation, localisation as well as therapeutic potential.

scholarly journals The Role of Exosomes in Bone Remodeling: Implications for Bone Physiology and Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Christos Masaoutis ◽  
Stamatios Theocharis
Keyword(s):  
Bone Remodeling ◽  
Current Knowledge ◽  
Active Role ◽  
Cell Types ◽  
Matrix Mineralization ◽  
Physiological Phenomenon ◽  
Health And Disease ◽  
Multiple Cell ◽  
Bone Physiology

Bone remodeling represents a physiological phenomenon of continuous bone tissue renewal that requires fine orchestration of multiple cell types, which is critical for the understanding of bone disease but not yet clarified in precise detail. Exosomes, which are cell-secreted nanovesicles drawing increasing attention for their broad biosignaling functions, can shed new light on how multiple heterogeneous cells communicate for the purpose of bone remodeling. In the healthy bone, exosomes transmit signals favoring both bone synthesis and resorption, regulating the differentiation, recruitment, and activity of most cell types involved in bone remodeling and even assuming an active role in extracellular matrix mineralization. Additionally, in the ailing bone, they actively participate in pathogenic processes constituting also potential therapeutic agents and drug vectors. The present review summarizes the current knowledge on bone exosomes and bone remodeling in health and disease.

scholarly journals Hsp110 mitigates α-synuclein pathology in vivo

2019 ◽  
Vol 116 (48) ◽  
pp. 24310-24316 ◽  
Author(s):  
Yumiko V. Taguchi ◽  
Erica L. Gorenberg ◽  
Maria Nagy ◽  
Drake Thrasher ◽  
Wayne A. Fenton ◽  
...  
Keyword(s):  
Cell Culture ◽  
Molecular Chaperones ◽  
Mammalian Cell Culture ◽  
Lewy Bodies ◽  
Cell Culture Model ◽  
Culture Model ◽  
Presynaptic Protein

Parkinson’s disease is characterized by the aggregation of the presynaptic protein α-synuclein and its deposition into pathologic Lewy bodies. While extensive research has been carried out on mediators of α-synuclein aggregation, molecular facilitators of α-synuclein disaggregation are still generally unknown. We investigated the role of molecular chaperones in both preventing and disaggregating α-synuclein oligomers and fibrils, with a focus on the mammalian disaggregase complex. Here, we show that overexpression of the chaperone Hsp110 is sufficient to reduce α-synuclein aggregation in a mammalian cell culture model. Additionally, we demonstrate that Hsp110 effectively mitigates α-synuclein pathology in vivo through the characterization of transgenic Hsp110 and double-transgenic α-synuclein/Hsp110 mouse models. Unbiased analysis of the synaptic proteome of these mice revealed that overexpression of Hsp110 can override the protein changes driven by the α-synuclein transgene. Furthermore, overexpression of Hsp110 is sufficient to prevent endogenous α-synuclein templating and spread following injection of aggregated α-synuclein seeds into brain, supporting a role for Hsp110 in the prevention and/or disaggregation of α-synuclein pathology.

scholarly journals Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis

2020 ◽  
Vol 117 (45) ◽  
pp. 27980-27988 ◽  
Author(s):  
Estefanía Lucendo ◽  
Mónica Sancho ◽  
Fabio Lolicato ◽  
Matti Javanainen ◽  
Waldemar Kulig ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Somatic Mutations ◽  
Transmembrane Domain ◽  
Active Role ◽  
Protein Family ◽  
Mitochondrial Outer Membrane ◽  
Dependent Manner ◽  
Mitochondrial Targeting ◽  
Carboxyl Terminal

The Bcl-2 protein family comprises both pro- and antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein family members can modulate apoptosis; however, the transmembrane interactome of the antiapoptotic protein Mcl-1 remains largely unexplored. Here, we demonstrate that the Mcl-1 TMD forms homooligomers in the mitochondrial membrane, competes with full-length Mcl-1 protein with regards to its antiapoptotic function, and induces cell death in a Bok-dependent manner. While the Bok TMD oligomers locate preferentially to the endoplasmic reticulum (ER), heterooligomerization between the TMDs of Mcl-1 and Bok predominantly takes place at the mitochondrial membrane. Strikingly, the coexpression of Mcl-1 and Bok TMDs produces an increase in ER mitochondrial-associated membranes, suggesting an active role of Mcl-1 in the induced mitochondrial targeting of Bok. Finally, the introduction of Mcl-1 TMD somatic mutations detected in cancer patients alters the TMD interaction pattern to provide the Mcl-1 protein with enhanced antiapoptotic activity, thereby highlighting the clinical relevance of Mcl-1 TMD interactions.

scholarly journals The β-Cell Genomic Landscape in T1D: Implications for Disease Pathogenesis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mireia Ramos-Rodríguez ◽  
Beatriz Pérez-González ◽  
Lorenzo Pasquali
Keyword(s):  
Regulatory Networks ◽  
Current Knowledge ◽  
Active Role ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Risk Variants ◽  
Genomic Landscape ◽  
External Stimuli

Abstract Purpose of Review Type 1 diabetes (T1D) develops as a consequence of a combination of genetic predisposition and environmental factors. Combined, these events trigger an autoimmune disease that results in progressive loss of pancreatic β cells, leading to insulin deficiency. This article reviews the current knowledge on the genetics of T1D with a specific focus on genetic variation in pancreatic islet regulatory networks and its implication to T1D risk and disease development. Recent Findings Accumulating evidence suggest an active role of β cells in T1D pathogenesis. Based on such observation several studies aimed in mapping T1D risk variants acting at the β cell level. Such studies unravel T1D risk loci shared with type 2 diabetes (T2D) and T1D risk variants potentially interfering with β-cell responses to external stimuli. Summary The characterization of regulatory genomics maps of disease-relevant states and cell types can be used to elucidate the mechanistic role of β cells in the pathogenesis of T1D.

scholarly journals Physiological and pathological roles of mitochondrial SLC25 carriers

2013 ◽  
Vol 454 (3) ◽  
pp. 371-386 ◽  
Author(s):  
Manuel Gutiérrez-Aguilar ◽  
Christopher P. Baines
Keyword(s):  
Mitochondrial Membrane ◽  
Current Knowledge ◽  
Transmembrane Helix ◽  
Building Blocks ◽  
Proper Function ◽  
Inner Mitochondrial Membrane ◽  
Health And Disease ◽  
Metabolic Reactions ◽  
Solute Carrier

The mitochondrion relies on compartmentalization of certain enzymes, ions and metabolites for the sake of efficient metabolism. In order to fulfil its activities, a myriad of carriers are properly expressed, targeted and folded in the inner mitochondrial membrane. Among these carriers, the six-transmembrane-helix mitochondrial SLC25 (solute carrier family 25) proteins facilitate transport of solutes with disparate chemical identities across the inner mitochondrial membrane. Although their proper function replenishes building blocks needed for metabolic reactions, dysfunctional SLC25 proteins are involved in pathological states. It is the purpose of the present review to cover the current knowledge on the role of SLC25 transporters in health and disease.

scholarly journals ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

2021 ◽  
Vol 22 (17) ◽  
pp. 9655
Author(s):  
Christian Koch ◽  
Maya Schuldiner ◽  
Johannes M. Herrmann
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Mitochondrial Membrane ◽  
Current Knowledge ◽  
Active Role ◽  
Mitochondrial Proteins ◽  
Receptor Proteins ◽  
Precursor Proteins ◽  
Surf Riding ◽  
Mitochondrial Membrane Protein

Most mitochondrial proteins are synthesized in the cytosol and targeted to the mitochondrial surface in a post-translational manner. The surface of the endoplasmic reticulum (ER) plays an active role in this targeting reaction. ER-associated chaperones interact with certain mitochondrial membrane protein precursors and transfer them onto receptor proteins of the mitochondrial surface in a process termed ER-SURF. ATP-driven proteins in the membranes of mitochondria (Msp1, ATAD1) and the ER (Spf1, P5A-ATPase) serve as extractors for the removal of mislocalized proteins. If the re-routing to mitochondria fails, precursors can be degraded by ER or mitochondria-associated degradation (ERAD or MAD respectively) in a proteasome-mediated reaction. This review summarizes the current knowledge about the cooperation of the ER and mitochondria in the targeting and quality control of mitochondrial precursor proteins.

Sign in / Sign up

Export Citation Format

Share Document