What Is Known about the Cause

2013 ◽  
Author(s):  
J. Eric Ahlskog
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Medical Center ◽  
Single Gene ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Early Years ◽  
Gene Coding ◽  
Sporadic Parkinson’S Disease ◽  
High Concentrations

Most of the research into the cause of Lewy disorders has focused on Parkinson’s disease, since that is the best defined of these conditions and, therefore, the most straightforward to study. Dementia with Lewy bodies (DLB) is more difficult to diagnose with certainty, especially in the early years of the disease. What we collectively learn about Parkinson’s disease will likely be very relevant to our understanding of DLB. Multiple investigations have linked Parkinson’s disease to both environmental exposures and genetic factors. However, these associations have all been modest, and none of them accounts for more than a few percent of the contribution to the cause of sporadic Parkinson’s disease (i.e., the attributable risks are low). These investigations are ongoing and hopefully will soon provide a more complete understanding of the cause(s). Perhaps the most important clue to all Lewy conditions is located in the brain: the Lewy body itself. A recent sophisticated analysis of Lewy bodies revealed approximately 300 different component proteins. However, we already knew that Lewy bodies contain high concentrations of a normal protein called alpha synuclein. In fact, Lewy bodies are conventionally identified under the microscope with antibody stains that specifically bind to alpha synuclein. Could this be the crucial protein among the nearly 300? While the alpha synuclein story is focused on Parkinson’s disease, it may be just as relevant to DLB, as we shall see. The story starts with a large Italian-American family with Parkinson’s disease, studied by Dr. Lawrence Golbe and colleagues at the Robert Wood Johnson Medical Center in New Brunswick, New Jersey. In this rare family, many members of multiple generations had been affected by Parkinson’s disease (with Lewy bodies), consistent with a single gene passed on with dominant inheritance. It took a number of years to identify that abnormal gene, which ultimately was proven to be the gene coding for alpha synuclein. It was quickly discovered that this genetic error is not present in usual cases of Parkinson’s disease.

scholarly journals Cryo-EM structure of alpha-synuclein fibrils

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ricardo Guerrero-Ferreira ◽  
Nicholas MI Taylor ◽  
Daniel Mona ◽  
Philippe Ringler ◽  
Matthias E Lauer ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Diagnosis And Treatment ◽  
Lewy Neurites ◽  
Cryo Electron Microscopy ◽  
High Concentrations ◽  
Hydrophobic Cleft

Parkinson’s disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1–121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50–57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.

scholarly journals TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains

2010 ◽  
Vol 19 (19) ◽  
pp. 3759-3770 ◽  
Author(s):  
Silvia Zucchelli ◽  
Marta Codrich ◽  
Federica Marcuzzi ◽  
Milena Pinto ◽  
Sandra Vilotti ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Sporadic Parkinson’S Disease

scholarly journals Alpha synuclein is present in Lewy bodies in sporadic Parkinson's disease

1998 ◽  
Vol 3 (6) ◽  
pp. 493-499 ◽  
Author(s):  
E Mezey ◽  
A M Dehejia ◽  
G Harta ◽  
S F Suchy ◽  
R L Nussbaum ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Sporadic Parkinson’S Disease

scholarly journals Erratum: Alpha synuclein is present in Lewy bodies in sporadic Parkinson's disease

1999 ◽  
Vol 4 (2) ◽  
pp. 197-197
Author(s):  
E Mezey ◽  
A M Dehejia ◽  
G Harta ◽  
N Tresser ◽  
S F Suchy ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Sporadic Parkinson’S Disease

scholarly journals The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 598
Author(s):  
Jeswinder Sian-Hulsmann ◽  
Peter Riederer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Viral Infections ◽  
Genetic Defect ◽  
Lewy Bodies ◽  
Common Denominator ◽  
Metabolic Disturbances ◽  
Trigger Factors ◽  
Protein Clearance ◽  
Sporadic Parkinson’S Disease

The risk of Parkinson’s disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson’s disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.

scholarly journals Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

2018 ◽  
Author(s):  
Tim E. Moors ◽  
Christina A. Maat ◽  
Daniel Niedieker ◽  
Daniel Mona ◽  
Dennis Petersen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Distribution Patterns ◽  
Alpha Synuclein ◽  
Label Free ◽  
Post Translational Modifications ◽  
Sted Microscopy ◽  
C Terminus

AbstractPost-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

scholarly journals Pathological Functions of LRRK2 in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2565
Author(s):  
Ga Ram Jeong ◽  
Byoung Dae Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Gene Encoding ◽  
Pathogenic Mutations ◽  
Abnormal Increase ◽  
Sporadic Parkinson’S Disease ◽  
Lrrk2 Kinase

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are common genetic risk factors for both familial and sporadic Parkinson’s disease (PD). Pathogenic mutations in LRRK2 have been shown to induce changes in its activity, and abnormal increase in LRRK2 kinase activity is thought to contribute to PD pathology. The precise molecular mechanisms underlying LRRK2-associated PD pathology are far from clear, however the identification of LRRK2 substrates and the elucidation of cellular pathways involved suggest a role of LRRK2 in microtubule dynamics, vesicular trafficking, and synaptic transmission. Moreover, LRRK2 is associated with pathologies of α-synuclein, a major component of Lewy bodies (LBs). Evidence from various cellular and animal models supports a role of LRRK2 in the regulation of aggregation and propagation of α-synuclein. Here, we summarize our current understanding of how pathogenic mutations dysregulate LRRK2 and discuss the possible mechanisms leading to neurodegeneration.

scholarly journals Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2289 ◽  
Author(s):  
Sanjanie Fernando ◽  
Claire Y. Allan ◽  
Katelyn Mroczek ◽  
Xavier Pearce ◽  
Oana Sanislav ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dictyostelium Discoideum ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Cell Cortex ◽  
Mutant Proteins ◽  
C Terminus

Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum.

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