☆ 4.3 Review

The 'α-synucleinopathy syndicate': multiple system atrophy and Parkinson's disease

JOURNAL OF NEURAL TRANSMISSION (2023)

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Article Clinical Neurology

Structural and metabolic correlates of neuropsychological profiles in multiple system atrophy and Parkinson's disease

Dorothee Kuebler et al.

Summary: This study explored the cognitive profiles in patients with Multiple System Atrophy with predominant parkinsonism (MSA-P) and Parkinson's disease (PD), and their relation to structural and metabolic changes in the frontostriatal region. The results showed that patients with MSA-P had deficits in executive function and higher levels of depression and anxiety compared to those with PD and healthy controls. Widespread frontal-striatal white matter damage and metabolic abnormalities were associated with cognitive dysfunction in both MSA-P and PD.

PARKINSONISM & RELATED DISORDERS (2023)

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Article Clinical Neurology

Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by alpha-synuclein conformations

Laura de Boni et al.

Summary: The equilibrium of alpha-synuclein conformations is destabilized in post-mortem human brain tissue of sporadic PD and DLB patients, showing disease-specific patterns. Destabilization of multimers leads to increased levels of pathological alpha-synuclein, while pharmacological stabilization leads to prion-like aggregation resistance. The destabilization of alpha-synuclein multimers may be caused by regional neuronal vulnerability and prion-like aggregation transmission.

ACTA NEUROPATHOLOGICA (2022)

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Review Biochemistry & Molecular Biology

Brain regions susceptible to alpha-synuclein spreading

Yu-Jie Guo et al.

Summary: This review explores the spreading of misfolded alpha-synuclein in animal models of Parkinson's disease and its association with motor dysfunction and neuronal death. Understanding the spread of alpha-synuclein is crucial for developing consistent PD animal models and future drug discovery efforts.

MOLECULAR PSYCHIATRY (2022)

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Article Multidisciplinary Sciences

Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy

Jacob I. Ayers et al.

Summary: Alpha-synuclein protein, with different conformations, is associated with neurodegenerative diseases including multiple system atrophy, dementia with Lewy bodies, and Parkinson's disease. Through experimental studies using transgenic mice and cultured cells, different strains of alpha-synuclein prions are found to be responsible for these diseases.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2022)

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Review Biochemistry & Molecular Biology

Initiation and progression of α-synuclein pathology in Parkinson's disease

George K. Tofaris

Summary: alpha-Synuclein aggregation is a critical molecular process in Parkinson's disease pathogenesis, and its nature influences the clinical heterogeneity. Alpha-synuclein assemblies need to exhibit seeding competency and toxicity for neurodegeneration to occur. It is currently unknown which alpha-synuclein assemblies are most relevant to the human condition.

CELLULAR AND MOLECULAR LIFE SCIENCES (2022)

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Review Biochemistry & Molecular Biology

Neuromelanin in Parkinson's Disease: Tyrosine Hydroxylase and Tyrosinase

Toshiharu Nagatsu et al.

Summary: Parkinson's disease is an aging-related neurodegenerative disease characterized by movement disorders and deficiency of dopamine. Lewy bodies and abnormal accumulation of neuromelanin are the histopathological hallmarks of Parkinson's disease, leading to cell death of dopamine neurons.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Article Neurosciences

Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease

Tushar Kamath et al.

Summary: In this study, single-cell genomics was used to analyze thousands of human dopamine neurons and identify a unique population susceptible to Parkinson's disease, which was enriched for genetic risk.

NATURE NEUROSCIENCE (2022)

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Article Psychiatry

Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy

Lluis Miquel-Rio et al.

Summary: Anxiety and depression affect 35-50% of Parkinson's disease (PD) patients and are related to dysfunction of the serotonergic system. Alpha-synuclein aggregates were found in brain tissues in the early stages of the disease.

TRANSLATIONAL PSYCHIATRY (2022)

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Article Neurosciences

Pathophysiological significance of increased α-synuclein deposition in sympathetic nerves in Parkinson's disease: a post-mortem observational study

Risa Isonaka et al.

Summary: Parkinson's disease is associated with increased alpha-synuclein deposition in the skin, submandibular gland, and myocardial tissues. This deposition does not seem to be pathogenic in the skin and submandibular gland, but it is highly significant in the heart.

TRANSLATIONAL NEURODEGENERATION (2022)

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Article Cell Biology

Pathological Relevance of Post-Translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson's Disease and Multiple System Atrophy

Berkiye Sonustun et al.

Summary: The predominant post-translational modifications of alpha-synuclein in the pathological process of idiopathic Parkinson's disease and multiple system atrophy were found to be phosphorylation and nitration, with phosphorylated alpha-synuclein being the earliest and most abundant form. These findings may have implications for the development of novel biomarkers and therapeutic approaches.

CELLS (2022)

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Article Clinical Neurology

Neuromelanin granules of the substantia nigra: proteomic profile provides links to tyrosine hydroxylase, stress granules and lysosomes

Maximilian Wulf et al.

Summary: Neuromelanin is a pigment present in neuromelanin granules (NMGs) in dopaminergic neurons. The function, origin, and synthesis of NMGs are still not fully understood. The study found a link between NMGs and lysosomes, as well as a high abundance of tyrosine hydroxylase in NMGs, which may be involved in neuromelanin synthesis. Additionally, a previously unknown connection between stress granules (SGs) and NMGs was discovered, potentially caused by oxidative stress from neuromelanin-bound metals.

JOURNAL OF NEURAL TRANSMISSION (2022)

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Article Clinical Neurology

Are there morphological differences between Parkinson's disease-dementia and dementia with Lewy bodies?

Kurt A. Jellinger

Summary: PDD and DLB are two major neurocognitive disorders in the spectrum of Lewy body diseases with overlapping clinical and neuropathological features. DLB has higher Braak LB scores and neuritic Braak stages, as well as more severe neuropathological features like Thal A beta phases and neuritic Braak stages. Worse prognosis in DLB is linked to increased Braak neuritic stages and more severe cerebral amyloid angiopathy.

PARKINSONISM & RELATED DISORDERS (2022)

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Article Multidisciplinary Sciences

Neuronal hyperactivity-induced oxidant stress promotes in vivo α-synuclein brain spreading

Michael Helwig et al.

Summary: This study revealed the influence of neuronal activity on the transfer of alpha-synuclein, with hyperactivity enhancing protein transfer and hypoactivity attenuating it. High neuronal activity exacerbated oxidative and nitrative reactions, leading to nitration of alpha-synuclein and increased protein aggregation. Mitochondria were identified as key targets and potential sources of reactive oxygen and nitrogen species within hyperactive neurons.

SCIENCE ADVANCES (2022)

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Review Clinical Neurology

Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease

P. Riederer et al.

Summary: Iron plays a crucial role in the pathogenesis and pathology of Parkinson's disease, with its involvement in early pathological processes. Aging is a major risk factor for PD, and dysfunction of the blood-brain barrier may contribute to the accumulation of iron in the substantia nigra area. The role of glial components in the pathogenesis of PD remains unclear.

JOURNAL OF NEURAL TRANSMISSION (2021)

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Article Neurosciences

Neuropathological evidence of body-first vs. brain-first Lewy body disease

Per Borghammer et al.

Summary: The aggregation of alpha-synuclein into inclusion bodies, known as Lewy pathology, is a key feature of Parkinson's disease and Dementia with Lewy bodies. Post mortem studies have shown that Lewy pathology follows two main distribution patterns in the brain, with some patients having pathogenic alpha-synuclein originating in the enteric nervous system and others originating inside the central nervous system.

NEUROBIOLOGY OF DISEASE (2021)

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Review Cell Biology

The Nigral Coup in Parkinson's Disease by α-Synuclein and Its Associated Rebels

Jeswinder Sian-Hulsmann et al.

Summary: The risk of developing Parkinson's disease increases with age, and the etiology of the disease remains unclear. Pathological changes, such as misfolded alpha-synuclein, play a key role in the disease's pathogenesis. Various factors combine to contribute to the development of Parkinson's disease, suggesting the need for consideration of multifactorial triggers and metabolic disturbances in drug development.

CELLS (2021)

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Article Clinical Neurology

Progression of phosphorylated α-synuclein in Macaca fuscata

Ito Kawakami et al.

Summary: The study found that synthetic human alpha-syn fibrils can spread throughout the brain of macaque monkeys via projection, association, and commissural fibers, although the progression of alpha-syn pathology is limited.

BRAIN PATHOLOGY (2021)

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Article Clinical Neurology

Significance of cerebral amyloid angiopathy and other co-morbidities in Lewy body diseases

Kurt A. Jellinger

Summary: LBD and PDD are two major neurocognitive disorders with Lewy bodies of unknown etiology, distinguished clinically based on the duration of Parkinsonism. Cerebral amyloid angiopathy (CAA) is increasingly recognized for its association with both pathologies and dementia. Recent studies imply the association of CAA, tau pathology, and LB pathology with cognitive decline and more rapid disease progression in LBD compared to PDD.

JOURNAL OF NEURAL TRANSMISSION (2021)

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Article Biochemistry & Molecular Biology

Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes

Hannah Scheiblich et al.

Summary: This study reveals that microglia form a cellular network to transfer and degrade alpha-synuclein fibrils, reducing inflammation and improving cell survival. This degradation strategy is compromised in cells carrying the LRRK2 G2019S mutation, highlighting a mechanism by which microglia enhance pathogenic alpha-synuclein clearance.

CELL (2021)

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Article Biochemistry & Molecular Biology

Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils

Karina Dauer nee Joppe et al.

Summary: Our study demonstrates that iron enrichment in the brain can reduce alpha-syn pathology and attenuate its spreading to specific brain regions, while also alleviating microglia accumulation in the striatum of mouse brains. The cognitive deficits induced by alpha-syn PFFs in mice seem to be independent of iron, suggesting a complex mechanism involving non-neuronal cells in the process of alpha-syn propagation.

JOURNAL OF NEUROCHEMISTRY (2021)

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Review Geriatrics & Gerontology

Alpha-Synuclein Post-translational Modifications: Implications for Pathogenesis of Lewy Body Disorders

Nelson de Oliveira Manzanza et al.

Summary: Lewy Body Disorders (LBDs) are age-related neurodegenerative diseases categorized as synucleinopathies, the second most common form of neurodegenerative dementias after Alzheimer's disease. There are currently no effective treatments for LBDs.

FRONTIERS IN AGING NEUROSCIENCE (2021)

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Article Biochemistry & Molecular Biology

Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation

Plamena R. Angelova et al.

CELL DEATH AND DIFFERENTIATION (2020)

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Article Clinical Neurology

Structure and efferences of the substantia nigra pars compacta in Parkinson's disease

Peter Urban et al.

FORTSCHRITTE DER NEUROLOGIE PSYCHIATRIE (2020)

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Review Clinical Neurology

The role of alpha-synuclein as ferrireductase in neurodegeneration associated with Parkinson's disease

Jeswinder Sian-Hulsmann et al.

JOURNAL OF NEURAL TRANSMISSION (2020)

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Correction Immunology

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation (Apri, 10.1038/s41590-020-0654-0, 2020)

Andrew S. Mendiola et al.

NATURE IMMUNOLOGY (2020)

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Article Clinical Neurology

Where and how alpha-synuclein pathology spreads in Parkinson's disease

Koichi Wakabayashi

NEUROPATHOLOGY (2020)

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Review Biochemistry & Molecular Biology

The Role of α-Synuclein Oligomers in Parkinson's Disease

Xiao-yu Du et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2020)

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Review Clinical Neurology

Is Braak staging valid for all types of Parkinson's disease?

Kurt A. Jellinger

JOURNAL OF NEURAL TRANSMISSION (2019)

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Article Neurosciences

Impairment of chaperone-mediated autophagy affects neuronal homeostasis through altered expression of DJ-1 and CRMP-2 proteins

Oeystein Roed Brekk et al.

MOLECULAR AND CELLULAR NEUROSCIENCE (2019)

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Review Clinical Neurology

Brain Iron Accumulation in Atypical Parkinsonian Syndromes: in vivo MRI Evidences for Distinctive Patterns

Jae-Hyeok Lee et al.

FRONTIERS IN NEUROLOGY (2019)

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Review Clinical Neurology

Neuropathology and pathogenesis of extrapyramidal movement disorders: a critical update-I. Hypokinetic-rigid movement disorders

Kurt A. Jellinger

JOURNAL OF NEURAL TRANSMISSION (2019)

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Review Clinical Neurology

α-Synuclein in Parkinson's disease: causal or bystander?

Peter Riederer et al.

JOURNAL OF NEURAL TRANSMISSION (2019)

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Article Neurosciences

Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease

Sangjune Kim et al.

NEURON (2019)

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Article Multidisciplinary Sciences

Cerebral mitochondrial electron transport chain dysfunction in multiple system atrophy and Parkinson's disease

Sandrine C. Foti et al.

SCIENTIFIC REPORTS (2019)

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Article Medicine, Research & Experimental

Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer

Ruth E. Musgrove et al.

JOURNAL OF CLINICAL INVESTIGATION (2019)

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Article Clinical Neurology

Slow Progressive Accumulation of Oligodendroglial Alpha-Synuclein (α-Syn) Pathology in Synthetic α-Syn Fibril-Induced Mouse Models of Synucleinopathy

Norihito Uemura et al.

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY (2019)

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Review Neurosciences

α-Synuclein pathology in Parkinson's disease and related α-synucleinopathies

Michael X. Henderson et al.

NEUROSCIENCE LETTERS (2019)

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Review Biochemistry & Molecular Biology

Models of multiple system atrophy

He-Jin Lee et al.

EXPERIMENTAL AND MOLECULAR MEDICINE (2019)

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Article Clinical Neurology

Oligodendroglial α-synucleinopathy-driven neuroinflammation in multiple system atrophy

Alana Hoffmann et al.

BRAIN PATHOLOGY (2019)

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Article Biochemistry & Molecular Biology

Parkinson's disease and multiple system atrophy have distinct α-synuclein seed characteristics

Tritia R. Yamasaki et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2019)

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Review Clinical Neurology

Dementia with Lewy bodies and Parkinson's disease-dementia: current concepts and controversies

Kurt A. Jellinger

JOURNAL OF NEURAL TRANSMISSION (2018)

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Article Medicine, Research & Experimental

alpha-Synuclein: Multiple System Atrophy Prions

Amanda L. Woerman et al.

COLD SPRING HARBOR PERSPECTIVES IN MEDICINE (2018)

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Review Neurosciences

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy

Kurt A. Jellinger

JOURNAL OF ALZHEIMERS DISEASE (2018)

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Review Neurosciences

The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint

Christine Kaindlstorfer et al.

JOURNAL OF ALZHEIMERS DISEASE (2018)

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Review Neurosciences

Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4+T Cells in Neurodegenerative Diseases

Helena Solleiro-Villavicencio et al.

FRONTIERS IN CELLULAR NEUROSCIENCE (2018)

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Article Biochemistry & Molecular Biology

Mitochondrial dysfunction in fibroblasts of Multiple System Atrophy

Giacomo Monzio Compagnoni et al.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE (2018)

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Article Multidisciplinary Sciences

The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy

Fumiko Kusunoki Nakamoto et al.

SCIENTIFIC REPORTS (2018)

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Review Clinical Neurology

Multiple system atrophy: insights into a rare and debilitating movement disorder

Florian Krismer et al.

NATURE REVIEWS NEUROLOGY (2017)

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Review Multidisciplinary Sciences

Multiple system atrophy: clinicopathological characteristics in Japanese patients

Tetsutaro Ozawa et al.

PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES (2017)

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Review Neurosciences

The Threshold Theory for Parkinson's Disease

Simone Engelender et al.

TRENDS IN NEUROSCIENCES (2017)

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Review Clinical Neurology

Multiple system atrophy: pathogenic mechanisms and biomarkers

Kurt A. Jellinger et al.

JOURNAL OF NEURAL TRANSMISSION (2016)

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Article Biochemical Research Methods

Purification of α-synuclein containing inclusions from human post mortem brain tissue

A. McCormack et al.

JOURNAL OF NEUROSCIENCE METHODS (2016)

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Review Clinical Neurology

Autophagy and Alpha-Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies

Maria Xilouri et al.

MOVEMENT DISORDERS (2016)

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Article Multidisciplinary Sciences

Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain

Wen Li et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2016)

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Article Multidisciplinary Sciences

Alterations of Myelin Content in Parkinson's Disease: A Cross-Sectional Neuroimaging Study

Douglas C. Dean et al.

PLOS ONE (2016)

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Review Clinical Neurology

Animal models of multiple system atrophy

Nadia Stefanova et al.

CLINICAL AUTONOMIC RESEARCH (2015)

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Review Neurosciences

Neuroinflammation in Multiple System Atrophy: Response to and Cause of α-Synuclein Aggregation

Bruno Di MarcoVieira et al.

FRONTIERS IN CELLULAR NEUROSCIENCE (2015)

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Article Clinical Neurology

Neuropathology of Multiple System Atrophy: New Thoughts About Pathogenesis

Kurt A. Jellinger

MOVEMENT DISORDERS (2014)

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Article Medicine, Research & Experimental

Multiple System Atrophy: Genetic or Epigenetic?

Edith Sturm et al.

Experimental Neurobiology (2014)

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Article Biochemistry & Molecular Biology

Modulation of ER stress and apoptosis by endoplasmic reticulum calcium leak via translocon during unfolded protein response: involvement of GRP78

Mehdi Hammadi et al.

FASEB JOURNAL (2013)

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Article Clinical Neurology

The natural history of multiple system atrophy: a prospective European cohort study

Gregor K. Wenning et al.

LANCET NEUROLOGY (2013)

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Article Clinical Neurology

Update on novel familial forms of Parkinson's disease and multiple system atrophy

Shinsuke Fujioka et al.

PARKINSONISM & RELATED DISORDERS (2013)

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Article Multidisciplinary Sciences

Transmission of multiple system atrophy prions to transgenic mice

Joel C. Watts et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2013)

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Review Neurosciences

The Role of Oxidative Stress in Parkinson's Disease

Vera Dias et al.

JOURNAL OF PARKINSONS DISEASE (2013)

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Article Biochemistry & Molecular Biology

The iNOS/Src/FAK axis is critical in Toll-like receptor-mediated cell motility in macrophages

Ming-Chei Maa et al.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH (2011)

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Article Clinical Neurology

Synuclein deposition and non-motor symptoms in Parkinson disease

Kurt A. Jellinger

JOURNAL OF THE NEUROLOGICAL SCIENCES (2011)

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Article Cell Biology

A novel molecular mechanism for nitrated α-synuclein-induced cell death

Yanying Liu et al.

JOURNAL OF MOLECULAR CELL BIOLOGY (2011)

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Article Neurosciences

Phosphorylation at S87 Is Enhanced in Synucleinopathies, Inhibits α-Synuclein Oligomerization, and Influences Synuclein-Membrane Interactions

Katerina E. Paleologou et al.

JOURNAL OF NEUROSCIENCE (2010)

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Article Multidisciplinary Sciences

Nitrated α-Synuclein Induces the Loss of Dopaminergic Neurons in the Substantia Nigra of Rats

Zhongwang Yu et al.

PLOS ONE (2010)

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Letter Clinical Neurology

Controversies over the staging of α-synuclein pathology in Parkinson's disease

Michail E. Kalaitzakis et al.

ACTA NEUROPATHOLOGICA (2008)

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Article Clinical Neurology

Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance

Laura Parkkinen et al.

ACTA NEUROPATHOLOGICA (2008)

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Editorial Material Clinical Neurology

Multiple system atrophy: A primary oligodendrogliopathy

Gregor K. Wenning et al.

ANNALS OF NEUROLOGY (2008)

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Article Clinical Neurology

Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy

J. Q. Trojanowski et al.

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY (2007)

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Review Clinical Neurology

TDP-43 in differential diagnosis of motor neuron disorders

Dennis W. Dickson et al.

ACTA NEUROPATHOLOGICA (2007)

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Article Biochemistry & Molecular Biology

Activation of the unfolded protein response in Parkinson's disease

J. J. M. Hoozemans et al.

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (2007)

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Article Neurosciences

Neurological and neurodegenerative alterations in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter:: Implications for multiple system atrophy

CW Shults et al.

JOURNAL OF NEUROSCIENCE (2005)

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Article Neurosciences

Mouse model of multiple system atrophy α-synuclein expression in oligodendrocytes causes glial and neuronal degeneration

I Yazawa et al.

NEURON (2005)

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Review Clinical Neurology

Diagnostic staging of Parkinson's disease:: conceptual aspects

H Przuntek et al.

JOURNAL OF NEURAL TRANSMISSION (2004)

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Review Neurosciences

Iron, brain ageing and neurodegenerative disorders

L Zecca et al.

NATURE REVIEWS NEUROSCIENCE (2004)

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Article Clinical Neurology

Nigral glutathione deficiency is not specific for idiopathic Parkinson's disease

PS Fitzmaurice et al.

MOVEMENT DISORDERS (2003)

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Article Clinical Neurology

Epidemiology of multiple system atrophy

N Vanacore et al.

NEUROLOGICAL SCIENCES (2001)

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