scholarly journals Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies

1999 ◽  
Vol 354 (1386) ◽  
pp. 1101-1118 ◽  
Author(s):  
Michel Goedert
Keyword(s):  
Neurodegenerative Diseases ◽  
Dementia With Lewy Bodies ◽  
Late Onset ◽  
Lewy Bodies ◽  
Corticobasal Degeneration ◽  
New Work ◽  
Missense Mutations ◽  
Protein Tau ◽  
Frontotemporal Dementias ◽  
Filamentous Inclusions

Alzheimer'sdisease and Parkinson'sdisease are the most common neurodegenerative diseases. They are characterized by the degeneration of selected populations of nerve cells that develop filamentous inclusions before degeneration. The neuronal inclusions of Alzheimer'sdisease are made of the microtubule–associated protein tau, in a hyperphosphorylated state. Recent work has shown that the filamentous inclusions of Parkinson'sdisease are made of the protein α–synuclein and that rare, familial forms of Parkinson'sdisease are caused by missense mutations in the α–synuclein gene. Besides Parkinson'sdisease, the filamentous inclusions of two additional neurodegenerative diseases, namely dementia with Lewy bodies and multiple system atrophy, have also been found to be made of α–synuclein. Abundant filamentous tau inclusions are not limited to Alzheimer'sdisease. They are the defining neuropathological characteristic of frontotemporal dementias such as Pick'sdisease, and of progressive supranuclear palsy and corticobasal degeneration. The recent discovery of mutations in the tau gene in familial forms of frontotemporal dementia has provided a direct link between tau dysfunction and dementing disease. The new work has established that tauopathies and α–synucleinopathies account for most late–onset neurodegenerative diseases in man. The formation of intracellular filamentous inclusions might be the gain of toxic function that leads to the demise of affected brain cells.

scholarly journals Structures of α-synuclein filaments from multiple system atrophy

2020 ◽  
Author(s):  
Manuel Schweighauser ◽  
Yang Shi ◽  
Airi Tarutani ◽  
Fuyuki Kametani ◽  
Alexey G. Murzin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Human Brain ◽  
Multiple System Atrophy ◽  
Recombinant Proteins ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Two Dimensional ◽  
Filamentous Inclusions

Synucleinopathies are human neurodegenerative diseases that include multiple system atrophy (MSA), Parkinson’s disease, Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) (1). Existing treatments are at best symptomatic. These diseases are characterised by the presence in brain cells of filamentous inclusions of α-synuclein, the formation of which is believed to cause disease (2, 3). However, the structures of α-synuclein filaments from human brain are not known. Here we show, using electron cryo-microscopy, that α-synuclein inclusions from MSA are made of two types of filaments, each of which consists of two different protofilaments. Non-proteinaceous molecules are present at the protofilament interfaces. By two-dimensional class averaging, we show that α-synuclein filaments from the brains of patients with MSA and DLB are different, suggesting that distinct conformers (or strains) characterise synucleinopathies. As was the case of tau assemblies (4–9), the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, with implications for understanding the mechanisms of aggregate propagation and neurodegeneration in human brain. These findings have diagnostic and potential therapeutic relevance, especially in view of the unmet clinical need to be able to image filamentous α-synuclein inclusions in human brain.

Neuropathology

2020 ◽  
pp. 77-98
Author(s):  
Johannes Attems ◽  
Kurt A. Jellinger
Keyword(s):  
Frontotemporal Lobar Degeneration ◽  
Dementia With Lewy Bodies ◽  
Prion Diseases ◽  
Hippocampal Sclerosis ◽  
Neurofibrillary Tangle ◽  
Lewy Bodies ◽  
Corticobasal Degeneration ◽  
Amyloid Angiopathy ◽  
Argyrophilic Grain ◽  
Cerebral Amyloid

This chapter describes the main neuropathological features of the most common age-associated neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and dementia with Lewy bodies, as well as other less frequent ones such as multiple system atrophy, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, neurofibrillary tangle-dominant dementia, frontotemporal lobar degeneration with TDP-43 pathology, and Huntington’s disease. Likewise, cerebral amyloid angiopathy, hippocampal sclerosis, vascular dementia, and prion diseases are described. A main aim of this chapter is to assist the reader in interpreting neuropathological reports; hence criteria for the neuropathological classifications of the major diseases are provided. One section covers general considerations on neurodegeneration, and basic pathophysiological mechanisms of tau, amyloid-β‎, α‎-synuclein, TDP-43, and prions are briefly described in the sections on the respective diseases. Finally, one section is dedicated to cerebral multimorbidity, and a view on currently emerging neuropathological methods is given.

scholarly journals Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Wenjuan Zhang ◽  
Benjamin Falcon ◽  
Alexey G Murzin ◽  
Juan Fan ◽  
R Anthony Crowther ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Neurodegenerative Diseases ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
The Third ◽  
In Vitro Assembly ◽  
Immuno Electron Microscopy ◽  
Structural Versatility ◽  
Filamentous Inclusions

Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer’s and Pick’s diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 2N4R tau assembles into multiple types of filaments, and the structures of three types reveal similar ‘kinked hairpin’ folds, in which the second and third repeats pack against each other. 2N3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack in a parallel manner. The heparin-induced tau filaments differ from those of Alzheimer’s or Pick’s disease, which have larger cores with different repeat compositions. Our results illustrate the structural versatility of amyloid filaments, and raise questions about the relevance of in vitro assembly.

scholarly journals Progressive Supranuclear Palsy: A Review of Co-existing Neurodegeneration

2008 ◽  
Vol 35 (5) ◽  
pp. 602-608 ◽  
Author(s):  
J Keith-Rokosh ◽  
L C Ang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Neurodegenerative Diseases ◽  
Progressive Supranuclear Palsy ◽  
Lewy Bodies ◽  
Corticobasal Degeneration ◽  
Pathological Changes ◽  
Subcortical Regions ◽  
Argyrophilic Grains

Objectives:The neuropathological findings of 32 progressive supranuclear palsy (PSP) cases over a period of 17 years were reviewed.Results:Of the 26 cases with adequate clinical data, 20 patients either presented with cognitive dysfunction or developed a cognitive impairment subsequently during the course of the disease. Co-existing changes of argyrophilic grains and corticobasal degeneration (CBD) were found in 28% and 32% of the cases respectively. Alzheimer-related pathology was found in 69% of cases but only 18.75% of cases fulfilled the consortium to establish a registry for Alzheimer's disease (CERAD) criteria for either definite or probable Alzheimer's disease. Lewy bodies were noted in four cases (12.5%), all in the subcortical regions. Only seven cases of PSP showed no pathological evidence of other co-existing neurodegenerative diseases. The severity of the cerebrovascular pathology in this cohort was insufficient to explain any clinical symptomatology.Conclusions:As in previous studies, this study has demonstrated the frequent co-existence of pathological changes usually noted in other neurodegenerative diseases in PSP. Whether these coexisting pathological changes contribute to the cognitive impairment in PSP remains uncertain.

Movement Disorders 2: Parkinson’s Plus and Degenerative Diseases (DRAFT)

2018 ◽  
Author(s):  
Tamara Kaplan ◽  
Tracey Milligan
Keyword(s):  
Huntington's Disease ◽  
Progressive Supranuclear Palsy ◽  
Movement Disorders ◽  
Dementia With Lewy Bodies ◽  
Wilson’S Disease ◽  
Lewy Bodies ◽  
Corticobasal Degeneration ◽  
Degenerative Diseases ◽  
Multiple Systems ◽  
Multiple Systems Atrophy

The video in this chapter explores movement disorders, and focuses on Parkinson’s Plus and degenerative diseases. It outlines the features and pathology of dementia with lewy bodies (DLB), progressive supranuclear palsy (PSP), multiple systems atrophy (MSA) and corticobasal degeneration (CBD), as well as genetic movement disorders, Wilson’s disease, and Huntington’s disease.

scholarly journals Dementia With Lewy Bodies: the Principles of Diagnostics, Treatment, and Management

Medicina ◽  
2012 ◽  
Vol 48 (1) ◽  
pp. 1 ◽  
Author(s):  
Jūratė Macijauskienė ◽  
Vita Lesauskaitė
Keyword(s):  
Dementia With Lewy Bodies ◽  
Management Strategies ◽  
Laboratory Data ◽  
Lewy Bodies ◽  
Corticobasal Degeneration ◽  
Later Life ◽  
Alpha Synuclein ◽  
Diagnostic Features ◽  
Protein Deposits ◽  
Diagnosis Of Dementia

Dementia with Lewy bodies was first recognized as a separate entity about 30 years ago. The prevalence varies from 0% to 5% in the general population, and this disease accounts for 0% to 30.5% of all dementia cases. Dementia with Lewy bodies is considered the second most common cause of degenerative dementia after Alzheimer’s disease. The disease is characterized by alpha-synuclein immunoreactive protein deposits in both neurons and glial cells. The protein deposits are especially prominent in dopaminergic neurons, where they can be detected using conventional histological stains, such as hematoxylin and eosin, and are commonly referred to as Lewy bodies. The diagnosis of dementia with Lewy bodies is based on the presence of dementia as well as 2 of the following 3 core diagnostic features: 1) fluctuating cognition, 2) visual hallucinations, and 3) movement disorder. Diagnostic tests include laboratory data, structural and functional imaging, and electroencephalography. Differential diagnosis of dementia with Lewy bodies focuses on other later life dementia syndromes, other parkinsonian diseases (Parkinson’s disease, progressive supranuclear palsy, corticobasal degeneration), and primary psychiatric illnesses. There is type 1b evidence to support treatment with cholinesterase inhibitors. Glutamatergic and dopaminergic therapies are used as well. Standard neuroleptics are contraindicated, and atypical agents should be used cautiously. Nonpharmacologic measures – therapeutic environment, psychological and social support, physical activity, behavioral management strategies, caregivers’ education and support, and different services – could be suggested.

Ventilatory Response to Hypercapnia Predicts Dementia with Lewy Bodies in Late-Onset Major Depressive Disorder

2016 ◽  
Vol 50 (3) ◽  
pp. 751-758 ◽  
Author(s):  
Sho Takahashi ◽  
Katsuyoshi Mizukami ◽  
Tetsuaki Arai ◽  
Ryoko Ogawa ◽  
Norihiro Kikuchi ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Dementia With Lewy Bodies ◽  
Late Onset ◽  
Ventilatory Response ◽  
Lewy Bodies ◽  
Major Depressive
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