A blood marker for Parkinson’s Disease: Neuronal exosome-derived α-synuclein

2021 ◽  
Author(s):  
Annika Kluge ◽  
Josina Bunk ◽  
Eva Schaeffer ◽  
Alice Drobny ◽  
Wei Xiang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Blood Plasma ◽  
Protein Misfolding ◽  
Blood Test ◽  
Plasma Samples ◽  
Blood Biomarker ◽  
Blood Marker ◽  
Amplification Assay ◽  
Β Sheet

Abstract To date, no reliable clinically applicable biomarker has been established for Parkinson’s disease (PD). Our results indicate that a long hoped blood test for Parkinson’s disease may be realized. We here assess the potential of pathological α-synuclein originating from neuron-derived exosomes from blood plasma as a possible biomarker. Following the isolation of neuron-derived exosomes from plasma of PD patients and non-PD individuals immunoblot analyses were performed to detect exosomal α-synuclein. Under native conditions significantly increased signals of disease-associated α-synuclein forms in neuron-derived exosomes were measured in all individuals with PD and clearly distinguished PD samples from controls. By performing a protein misfolding cyclic amplification assay these aggregates could be amplified and seeding could be demonstrated. Moreover, the aggregates exhibited β-sheet-rich structures and showed a fibrillary appearance. Our study demonstrates that the detection of pathological α-synuclein conformers from neuron-derived exosomes from plasma samples has the potential of a promising blood-biomarker of PD.

scholarly journals Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

2021 ◽  
pp. 1-10
Author(s):  
Vera Kovaleva ◽  
Mart Saarma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Er Stress ◽  
Protein Misfolding ◽  
Drug Targets ◽  
Dopamine Neurons ◽  
Drug Candidates ◽  
The Unfolded Protein Response

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.

scholarly journals Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein

2019 ◽  
Vol 116 (36) ◽  
pp. 17963-17969 ◽  
Author(s):  
Katsuya Araki ◽  
Naoto Yagi ◽  
Koki Aoyama ◽  
Chi-Jing Choong ◽  
Hideki Hayakawa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
X Ray Diffraction ◽  
Thin Sections ◽  
X Ray ◽  
Β Sheet ◽  
The Brain

Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson’s disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-β structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-β sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-β structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-β structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of α-syn.

scholarly journals Heme minimizes Parkinson’s disease-associated toxicity by inducing a conformational distortion in the oligomers of alpha-Synuclein

2019 ◽  
Author(s):  
Ritobrita Chakraborty ◽  
Sandip Dey ◽  
Simanta Sarani Paul ◽  
Pallabi Sil ◽  
Jayati Sengupta ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intrinsically Disordered Protein ◽  
Alpha Synuclein ◽  
Oligomeric State ◽  
Intrinsically Disordered ◽  
Nmr Study ◽  
Novel Strategy ◽  
Structural Architecture ◽  
Β Sheet

AbstractAggregation of the intrinsically disordered protein alpha-Synuclein (α-Syn) into insoluble fibrils with a cross-β sheet amyloid structure plays a key role in the neuronal pathology of Parkinson’s disease (PD). The fibrillation pathway of α-Syn encompasses a multitude of transient oligomeric forms differing in size, secondary structure, hydrophobic exposure and toxicity. According to a recent solid state NMR study, the fibrillating unit of α-Syn contains the core residues of the protein arranged into in-register parallel β sheets with a unique Greek key topology. Here, we have shown that the physiologically available small molecule heme (hemin chloride) when added at sub-stoichiometric ratios to either monomeric or aggregated α-Syn, arrests its aggregation in an oligomeric state, which is minimally toxic. Using cryo-EM, we observed that these heme-induced oligomers are ‘mace’-shaped and consist of approximately four monomers. However, the presence of a crucial twist or contortion in their Greek key structural architecture prevents further hierarchical appending into annular oligomers and protofilament formation. We confirm using a His50Gln mutant that the binding of heme onto His50 is crucial in inflicting the structural distortion and is responsible for the stabilization of the non-toxic and off-pathway α-Syn oligomers. We believe that this study provides a novel strategy of developing a therapeutic solution of PD, which has been elusive so far.

scholarly journals Ubiquitin and Parkinson's disease through the looking glass of genetics

2017 ◽  
Vol 474 (9) ◽  
pp. 1439-1451 ◽  
Author(s):  
Helen Walden ◽  
Miratul M.K. Muqit
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Neuronal Loss ◽  
Protein Quality Control ◽  
Biochemical Alterations ◽  
Ubiquitin System ◽  
Novel Therapeutic Strategies

Biochemical alterations found in the brains of Parkinson's disease (PD) patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signalling plays a central role in protein quality control; however, prior to genetic advances, the detailed mechanisms of how impairment in the ubiquitin system was linked to PD remained mysterious. The discovery of mutations in the α-synuclein gene, which encodes the main protein misfolded in PD aggregates, together with mutations in genes encoding ubiquitin regulatory molecules, including PTEN-induced kinase 1 (PINK1), Parkin, and FBX07, has provided an opportunity to dissect out the molecular basis of ubiquitin signalling disruption in PD, and this knowledge will be critical for developing novel therapeutic strategies in PD that target the ubiquitin system.

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