scholarly journals Multiplicity of α-Synuclein Aggregated Species and Their Possible Roles in Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8043 ◽  
Author(s):  
Pablo Gracia ◽  
José D. Camino ◽  
Laura Volpicelli-Daley ◽  
Nunilo Cremades
Keyword(s):  
Multiple System Atrophy ◽  
Neurodegenerative Disorders ◽  
Lewy Body ◽  
Lewy Body Dementia ◽  
Therapeutic Interventions ◽  
Amyloid Aggregation ◽  
Intermediate Species ◽  
Molecular Feature ◽  
Nucleation Mechanisms ◽  
Disease Specific

α-Synuclein amyloid aggregation is a defining molecular feature of Parkinson’s disease, Lewy body dementia, and multiple system atrophy, but can also be found in other neurodegenerative disorders such as Alzheimer’s disease. The process of α-synuclein aggregation can be initiated through alternative nucleation mechanisms and dominated by different secondary processes giving rise to multiple amyloid polymorphs and intermediate species. Some aggregated species have more inherent abilities to induce cellular stress and toxicity, while others seem to be more potent in propagating neurodegeneration. The preference for particular types of polymorphs depends on the solution conditions and the cellular microenvironment that the protein encounters, which is likely related to the distinct cellular locations of α-synuclein inclusions in different synucleinopathies, and the existence of disease-specific amyloid polymorphs. In this review, we discuss our current understanding on the nature and structure of the various types of α-synuclein aggregated species and their possible roles in pathology. Precisely defining these distinct α-synuclein species will contribute to understanding the molecular origins of these disorders, developing accurate diagnoses, and designing effective therapeutic interventions for these highly debilitating neurodegenerative diseases.

Pathogenesis of Lewy Body Dementia

2017 ◽  
Author(s):  
Jagan A. Pillai ◽  
James B. Leverenz
Keyword(s):  
Cognitive Impairment ◽  
Neurodegenerative Disorders ◽  
Lewy Body ◽  
Genetic Factors ◽  
Lewy Bodies ◽  
Lewy Body Dementia ◽  
Therapeutic Interventions ◽  
Cognitive Changes ◽  
Lewy Neurites ◽  
Neuronal Processes

This chapter discusses the Pathogenesis of Lew Body Dementia. The Lewy body dementias (LBDs) are a spectrum of dementing neurodegenerative disorders underpinned by the pathological accumulation of α- synuclein protein in both intraneuronal inclusions, “Lewy bodies, ” and neuronal processes, “Lewy neurites”. The chapter concludes that, as with other forms of cognitive impairment in the aged, the pathophysiology of cognitive impairment in LBD is likely multifactorial. Although it appears that α- synuclein pathology, particularly in the limbic and neocortical regions are linked to cognitive changes, other pathologies such as AD likely also play a role. Emphasizing the complexity, a number of genetic factors have been implicated in the LBDs, some specifically with associations to the synucleinopathies and some with other pathophysiologic processes. This complexity will need to be considered as therapeutic interventions are evaluated for the LBD.

scholarly journals The emerging role of α-synuclein truncation in aggregation and disease

2020 ◽  
Vol 295 (30) ◽  
pp. 10224-10244 ◽  
Author(s):  
Zachary A. Sorrentino ◽  
Benoit I. Giasson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Lewy Body ◽  
Critical Role ◽  
Lewy Body Dementia ◽  
Proteolytic Processing ◽  
Neuronal Protein ◽  
Preventative Strategy

α-Synuclein (αsyn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. These fibrils may induce further αsyn misfolding and propagation of pathologic fibrils in a prion-like process. It is unclear why αsyn initially misfolds, but a growing body of literature suggests a critical role of partial proteolytic processing resulting in various truncations of the highly charged and flexible carboxyl-terminal region. This review aims to 1) summarize recent evidence that disease-specific proteolytic truncations of αsyn occur in Parkinson's disease, Lewy body dementia, and multiple system atrophy and animal disease models; 2) provide mechanistic insights on how truncation of the amino and carboxyl regions of αsyn may modulate the propensity of αsyn to pathologically misfold; 3) compare experiments evaluating the prion-like properties of truncated forms of αsyn in various models with implications for disease progression; 4) assess uniquely toxic properties imparted to αsyn upon truncation; and 5) discuss pathways through which truncated αsyn forms and therapies targeted to interrupt them. Cumulatively, it is evident that truncation of αsyn, particularly carboxyl truncation that can be augmented by dysfunctional proteostasis, dramatically potentiates the propensity of αsyn to pathologically misfold into uniquely toxic fibrils with modulated prion-like seeding activity. Therapeutic strategies and experimental paradigms should operate under the assumption that truncation of αsyn is likely occurring in both initial and progressive disease stages, and preventing truncation may be an effective preventative strategy against pathologic inclusion formation.

scholarly journals Dopamine cell loss in the periaqueductal gray in multiple system atrophy and Lewy body dementia

Neurology ◽  
2009 ◽  
Vol 73 (2) ◽  
pp. 106-112 ◽  
Author(s):  
E. E. Benarroch ◽  
A. M. Schmeichel ◽  
B. N. Dugger ◽  
P. Sandroni ◽  
J. E. Parisi ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Body ◽  
Lewy Body Dementia ◽  
Cell Loss ◽  
Periaqueductal Gray ◽  
Dopamine Cell

scholarly journals The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure

2020 ◽  
Vol 117 (7) ◽  
pp. 3592-3602 ◽  
Author(s):  
David R. Boyer ◽  
Binsen Li ◽  
Chuanqi Sun ◽  
Weijia Fan ◽  
Kang Zhou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Lewy Body Dementia ◽  
Salt Bridge ◽  
Wild Type ◽  
Molecular Feature ◽  
Multiple Systems ◽  
Fibril Structure

Aggregation of α-synuclein is a defining molecular feature of Parkinson’s disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson’s disease and Lewy body dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy body dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5-Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly rearranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which form the E46-K80 salt bridge in the wild-type fibril structure. We hypothesize that, under our conditions, the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap—a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.

Mesopontine cholinergic neuron involvement in Lewy body dementia and multiple system atrophy

Neurology ◽  
2008 ◽  
Vol 70 (5) ◽  
pp. 368-373 ◽  
Author(s):  
A. M. Schmeichel ◽  
L. C. Buchhalter ◽  
P. A. Low ◽  
J. E. Parisi ◽  
B. W. Boeve ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Body ◽  
Lewy Body Dementia ◽  
Cholinergic Neuron

Social inappropriateness in neurodegenerative disorders

2017 ◽  
Vol 30 (2) ◽  
pp. 197-207 ◽  
Author(s):  
Philippe Desmarais ◽  
Krista L. Lanctôt ◽  
Mario Masellis ◽  
Sandra E. Black ◽  
Nathan Herrmann
Keyword(s):  
Social Cognition ◽  
Neurodegenerative Disorders ◽  
Neuropsychiatric Symptoms ◽  
Lewy Body Dementia ◽  
Mental States ◽  
Brain Regions ◽  
Self Control ◽  
Therapeutic Interventions ◽  
Neural Basis ◽  
Aged Patients

ABSTRACTBackground:New onset of mood and behavioral changes in middle-aged patients are frequently the first manifestations of an unrecognized neurocognitive disorder. Impairment of social cognition, the cognitive ability to process social information coming from others, such as emotions, to attribute mental states to others, and to respond appropriately to them, is often at the origin of behavioral manifestations in neurodegenerative disorders.Methods:This paper reviews the current literature on social cognition impairment in neurocognitive disorders, particularly in prodromal stages of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), idiopathic Parkinson's disease (IPD), and Lewy body dementia (LBD). The concepts of social cognition will be reviewed, including its impairment and neural basis, its clinical assessment, and the different therapeutic interventions available clinically.Results:Socially inappropriate behaviors, such as loss of empathy, inappropriateness of affect, and disinhibition are frequently reported in prodromal bvFTD and in prodromal AD. Lack of self-control, reduced perception of social cues, such as recognition of facial emotions and sarcastic speech, and impaired Theory of Mind all contribute to the neuropsychiatric symptoms and are secondary to neurodegeneration in specific brain regions. In contrasts to bvFTD and AD, deficits in social cognition in IPD occur later in the course of the disease and are often multifactorial in origin.Conclusions:Through various manifestations, social inappropriateness is frequently the first clinical sign of a neurodegenerative process, especially in AD and bvFTD, years before noticeable impairment on classical neuropsychological assessment and brain atrophy on imaging.

Rostral raphe involvement in Lewy body dementia and multiple system atrophy

2007 ◽  
Vol 114 (3) ◽  
pp. 213-220 ◽  
Author(s):  
E. E. Benarroch ◽  
A. M. Schmeichel ◽  
P. Sandroni ◽  
J. E. Parisi ◽  
P. A. Low
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Body ◽  
Lewy Body Dementia

Lewy Body Dementia

2005 ◽  
Vol 10 (2) ◽  
pp. 7-10 ◽  
Author(s):  
Susan Goldfein ◽  
Constance Dean Qualls
Keyword(s):  
Lewy Body ◽  
Lewy Body Dementia

scholarly journals Imaging Familial and Sporadic Neurodegenerative Disorders Associated with Parkinsonism

2021 ◽  
Author(s):  
David J. Brooks
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorders ◽  
Lewy Body Dementia ◽  
Imaging Biomarkers ◽  
Imaging Findings ◽  
Subclinical Disease ◽  
Similarities And Differences ◽  
Potential Use

AbstractIn this paper, the structural and functional imaging changes associated with sporadic and genetic Parkinson’s disease and atypical Parkinsonian variants are reviewed. The role of imaging for supporting diagnosis and detecting subclinical disease is discussed, and the potential use and drawbacks of using imaging biomarkers for monitoring disease progression is debated. Imaging changes associated with nonmotor complications of PD are presented. The similarities and differences in imaging findings in Lewy body dementia, Parkinson’s disease dementia, and Alzheimer’s disease are discussed.

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