Epigenetics of the Synapse in Neurodegeneration Xylaki, Mary; Atzler, Benedict; Outeiro, Tiago Fleming
Current neurology and neuroscience reports,
10/2019, Letnik:
19, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Purpose of Review
In the quest for understanding the pathophysiological processes underlying degeneration of nervous systems, synapses are emerging as sites of great interest as synaptic dysfunction ...is thought to play a role in the initiation and progression of neuronal loss. In particular, the synapse is an interesting target for the effects of epigenetic mechanisms in neurodegeneration. Here, we review the recent advances on epigenetic mechanisms driving synaptic compromise in major neurodegenerative disorders.
Recent Findings
Major developments in sequencing technologies enabled the mapping of transcriptomic patterns in human postmortem brain tissues in various neurodegenerative diseases, and also in cell and animal models. These studies helped identify changes in classical neurodegeneration pathways and discover novel targets related to synaptic degeneration.
Summary
Identifying epigenetic patterns indicative of synaptic defects prior to neuronal degeneration may provide the basis for future breakthroughs in the field of neurodegeneration.
β-Glucocerebrosidase (GCase) mutations lead to glucosylceramide build-up in the lysosome, impacting α-synuclein aggregation and autophagy. Recently, Baden and colleagues found GCase in mitochondria, ...supporting mitochondrial complex I function and energy metabolism. We believe the newly described role of GCase in the mitochondria will inform new Parkinson’s and Gaucher’s disease therapeutics.
Alpha-synuclein is implicated in several neurodegenerative disorders, such as Parkinson's disease and multiple system atrophy, yet its functions remain obscure. When expressed in yeast, ...alpha-synuclein associated with the plasma membrane in a highly selective manner, before forming cytoplasmic inclusions through a concentration-dependent, nucleated process. Alpha-synuclein inhibited phospholipase D, induced lipid droplet accumulation, and affected vesicle trafficking. This readily manipulable system provides an opportunity to dissect the molecular pathways underlying normal alpha-synuclein biology and the pathogenic consequences of its misfolding.
Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB ...is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson's disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as disease progresses, there has been controversy about the separation of DLB from PD dementia (PDD) and consensus reports have put forward guidelines to assist clinicians in the identification and management of both syndromes. Here, we present basic concepts and definitions, based on our current understanding, that should guide the community to address open questions that will, hopefully, lead us towards improved diagnosis and novel therapeutic strategies for DLB and other synucleinopathies.
The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of synuclein and related human ...conditions with the goal of discussing and advancing the research. In 2019, the Synuclein Meeting is taking place in Ofir, a city in the outskirts of Porto, Portugal. The meeting is entitled ‘Synuclein Meeting 2019: Where we are and where we need to go’. It has now been 22 years since the initial report of the genetic and pathological association between alpha‐synuclein and Parkinson’s disease (PD). The field has grown and matured, and major advances have been made. We are witnessing exciting times, with the first clinical trials being conducted that target synuclein, and bring the hope of novel therapies for patients with PD and their families. However, we still face many challenges and need to address fundamental questions for the field to progress to where we need to go: having biomarkers and effective therapies for PD and other synucleinopathies. In this context, we have designed the Synuclein Meeting 2019 with a different format. The program will include sessions in the format of a round‐table discussion, to break away from the more rigid format of regular scientific meetings based on oral presentations. Our goal was to create opportunities for discussing the major questions in the field of synuclein and related human disorders, and challenge dogmatic ideas that require a critical revision in light of the most recent knowledge. In this issue, we assembled a series of comprehensive overviews of major topics, questions, and challenges in the field, that will be discussed in the meeting. We are confident that this special issue will be an instrumental reference for inspiring novel paths for future discoveries in the synuclein field and generate other discussions in the scientific community.
This is the Preface for the Special Issue “Synuclein”.
Cover Image for this issue: doi: 10.1111/jnc.14520.
It has now been 22 years since the initial report of the genetic and pathological association between alpha‐synuclein (aSyn) and Parkinson’s disease (PD). The field has grown and matured, and major advances have been made. We are witnessing exciting times, with major ongoing (and future) clinical trials that bring hope to patients with PD and their families. However, we still face many challenges and need to address fundamental questions so that the filed can progress to where we would like it to be. In this issue, we assembled a series of comprehensive overviews of major topics, questions, and challenges in the field, and we hope they are useful for guiding the path for future discoveries. This special issue is related, but not limited, to the Synuclein Meetings, a conference series that has been taking place every ~ 2 years for the past ~ 12 years, that bring together the leading experts in the field with the goal of discussing and advancing the research in the field. This year, the meeting is entitled ‘Synuclein Meeting 2019: Where we are and where we need to go’.
This is the Preface for the Special Issue “Synuclein”.
Cover Image for this issue: doi: 10.1111/jnc.14520.
Parkinson’s disease is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha-synuclein in intraneuronal inclusions known as Lewy bodies and Lewy neurites. ...Multiple studies strongly implicate the levels of alpha-synuclein as a major risk factor for the onset and progression of Parkinson’s disease. Alpha-synuclein pathology spreads progressively throughout interconnected brain regions but the precise molecular mechanisms underlying the seeding of alpha-synuclein aggregation are still unclear. Here, using stable cell lines expressing alpha-synuclein, we examined the correlation between endogenous alpha-synuclein levels and the seeding propensity by exogenous alpha-synuclein preformed fibrils. We applied biochemical approaches and imaging methods in stable cell lines expressing alpha-synuclein and in primary neurons to determine the impact of alpha-synuclein levels on seeding and aggregation. Our results indicate that the levels of alpha-synuclein define the pattern and severity of aggregation and the extent of p-alpha-synuclein deposition, likely explaining the selective vulnerability of different cell types in synucleinopathies. The elucidation of the cellular processes involved in the pathological aggregation of alpha-synuclein will enable the identification of novel targets and the development of therapeutic strategies for Parkinson’s disease and other synucleinopathies.
Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a‐synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with ...Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019: Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.
This article is related to the Special Issue Synuclein which was solicited from the Synuclein Meeting 2019. Every 2 years for about 12 years, the Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. Alpha‐synuclein (aSyn) is implicated in several neurodegenerative disorders of the brain and in this review we cover various aspects of aSyn biology and pathobiology, as depicted in the various circles.
This article is related to the Special Issue "Synuclein"
The budding yeast, Saccharomyces cerevisiae, is the best‐studied eukaryotic cell, at both genetic and physiological levels. As a eukaryote, yeast shares highly conserved molecular and cellular ...mechanisms with human cells. Thus, this simple fungus is an invaluable model to study the fundamental molecular mechanisms involved in several human diseases. In the particular case of neurodegenerative disorders, yeast models have been able to recapitulate several important features of complex and devastating disorders, such as Huntington's and Parkinson's diseases. Once validated, these models have also been used to accelerate the identification of both novel therapeutic targets and compounds with therapeutic potential. Here, we review the recent contributions of this simple, but powerful model organism toward our understanding of neurodegeneration.
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