scholarly journals The G2385R risk factor for Parkinson's disease enhances CHIP-dependent intracellular degradation of LRRK2

2017 ◽  
Vol 474 (9) ◽  
pp. 1547-1558 ◽  
Author(s):  
Iakov N. Rudenko ◽  
Alice Kaganovich ◽  
Rebekah G. Langston ◽  
Aleksandra Beilina ◽  
Kelechi Ndukwe ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Steady State ◽  
Proteasomal Degradation ◽  
Wild Type ◽  
Intracellular Protein ◽  
Protein Levels ◽  
Intracellular Degradation

Autosomal dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD). Most pathogenic LRRK2 mutations result in amino acid substitutions in the central ROC (Ras of complex proteins)–C-terminus of ROC–kinase triple domain and affect enzymatic functions of the protein. However, there are several variants in LRRK2, including the risk factor G2385R, that affect PD pathogenesis by unknown mechanisms. Previously, we have shown that G2385R LRRK2 has decreased kinase activity in vitro and altered affinity to LRRK2 interactors. Specifically, we found an increased binding to the chaperone Hsp90 (heat shock protein 90 kDa) that is known to stabilize LRRK2, suggesting that G2385R may have structural effects on LRRK2. In the present study, we further explored the effects of G2385R on LRRK2 in cells. We found that G2385R LRRK2 has lower steady-state intracellular protein levels compared with wild-type LRRK2 due to increased protein turnover of the mutant protein. Mechanistically, this is a consequence of a higher affinity of G2385R compared with the wild-type protein for two proteins involved in proteasomal degradation, Hsc70 and carboxyl-terminus of Hsc70-interacting protein (CHIP). Overexpression of CHIP decreased intracellular protein levels of both G2385R mutant and wild-type LRRK2, while short interfering RNA CHIP knockdown had the opposite effect. We suggest that the G2385R substitution tilts the equilibrium between refolding and proteasomal degradation toward intracellular degradation. The observation of lower steady-state protein levels may explain why G2385R is a risk factor rather than a penetrant variant for inherited PD.

scholarly journals Familial Parkinson's Disease Mutant E46K α-Synuclein Localizes to Membranous Structures, Forms Aggregates, and Induces Toxicity in Yeast Models

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Michael Fiske ◽  
Michael White ◽  
Stephanie Valtierra ◽  
Sara Herrera ◽  
Keith Solvang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Plasma Membrane ◽  
Mutant Form ◽  
Phospholipid Membrane ◽  
Endomembrane System ◽  
Wild Type ◽  
Significant Toxicity ◽  
Familial Parkinson’S Disease

In Parkinson’s disease (PD), midbrain dopaminergic neuronal death is linked to the accumulation of aggregated α-synuclein. The familial PD mutant form of α-synuclein, E46K, has not been thoroughly evaluated yet in an organismal model system. Here, we report that E46K resembled wild-type (WT) α-synuclein in Saccharomyces cerevisiae in that it predominantly localized to the plasma membrane, and it did not induce significant toxicity or accumulation. In contrast, in Schizosaccharomyces pombe, E46K did not associate with the plasma membrane. Instead, in one strain, it extensively aggregated in the cytoplasm and was as toxic as WT. Remarkably, in another strain, E46K extensively associated with the endomembrane system and was more toxic than WT. Our studies recapitulate and extend aggregation and phospholipid membrane association properties of E46K previously observed in vitro and cell culture. Furthermore, it supports the notion that E46K generates toxicity partly due to increased association with endomembrane systems within cells.

scholarly journals Longevity factor klotho and resistance to cognitive deficits in a transgenic mouse model and in individuals with Parkinson’s disease

2020 ◽  
Author(s):  
Arturo Moreno ◽  
Nijee Luthra ◽  
Luke Bonham ◽  
Jonathan Lin ◽  
Lauren Broestl ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Cognitive Impairment ◽  
Steady State ◽  
Cognitive Deficits ◽  
Genetic Variant ◽  
Transgenic Mouse Model ◽  
Primary Risk Factor ◽  
Related Mortality

Abstract Aging is the primary risk factor for Parkinson’s disease (PD) and cognitive impairment from PD is a major and unmet biomedical challenge. Klotho, a pleiotropic protein, extends lifespan and enhances cognition. Whether longevity factors such as klotho can counteract PD-related mortality and deficits in mice or associate with resistance to PD in humans is unknown. Here we show that transgenic elevation of klotho increased lifespan, improved synaptic and cognitive, but not motor, functions in mice, and decreased steady state α-synuclein levels in the brains of mice that express wildtype human α-synuclein. In humans, a genetic variant of KLOTHO that increases circulating klotho levels associated with better executive cognition and less CSF abnormalities of α-synuclein in individuals with PD. Thus, klotho can counteract cognitive deficits related to PD, possibly modulating α-synuclein levels – and these findings may be relevant to new therapeutic pathways for human PD.

Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2845-2859 ◽  
Author(s):  
Jun Sung Lee ◽  
Kazuaki Kanai ◽  
Mari Suzuki ◽  
Woojin S Kim ◽  
Han Soo Yoo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Modifier ◽  
Ectopic Expression ◽  
Physical Interaction ◽  
Dependent Manner ◽  
Arylsulfatase A ◽  
Lysosomal Storage ◽  
Protein Levels

AbstractMutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson’s disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson’s disease. Plasma ARSA protein levels were changed in Parkinson’s disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson’s disease pathogenesis, acting as a molecular chaperone for α-synuclein.

scholarly journals Parkinson’s disease recovery by GM1 oligosaccharide treatment in the B4galnt1+/− mouse model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Elena Chiricozzi ◽  
Laura Mauri ◽  
Giulia Lunghi ◽  
Erika Di Biase ◽  
Maria Fazzari ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Potential ◽  
Physical Symptoms ◽  
Wild Type ◽  
Ganglioside Content ◽  
Sporadic Parkinson’S Disease ◽  
Specific Membrane ◽  
The Brain

AbstractGiven the recent in vitro discovery that the free soluble oligosaccharide of GM1 is the bioactive portion of GM1 for neurotrophic functions, we investigated its therapeutic potential in the B4galnt1+/− mice, a model of sporadic Parkinson’s disease. We found that the GM1 oligosaccharide, systemically administered, reaches the brain and completely rescues the physical symptoms, reduces the abnormal nigral α-synuclein content, restores nigral tyrosine hydroxylase expression and striatal neurotransmitter levels, overlapping the wild-type condition. Thus, this study supports the idea that the Parkinson’s phenotype expressed by the B4galnt1+/− mice is due to a reduced level of neuronal ganglioside content and lack of interactions between the oligosaccharide portion of GM1 with specific membrane proteins. It also points to the therapeutic potential of the GM1 oligosaccharide for treatment of sporadic Parkinson’s disease.

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.

scholarly journals Magnolol Protects against MPTP/MPP+-Induced Toxicity via Inhibition of Oxidative Stress inIn VivoandIn VitroModels of Parkinson’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Akiko Muroyama ◽  
Aya Fujita ◽  
Cheng Lv ◽  
Shota Kobayashi ◽  
Yoshiyasu Fukuyama ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oxygen Species ◽  
Protective Effects ◽  
Human Neuroblastoma ◽  
Protein Levels ◽  
Mptp Treatment

The aim of this study is to investigate the role of magnolol in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-) induced neurodegeneration in mice and 1-methyl-4-phenylpyridinium ion-(MPP+-) induced cytotoxicity to human neuroblastoma SH-SY5Y cells and to examine the possible mechanisms. Magnolol (30 mg/kg) was orally administered to C57BL/6N mice once a day for 4 or 5 days either before or after MPTP treatment. Western blot analysis revealed that MPTP injections substantially decreased protein levels of dopamine transporter (DAT) and tyrosine hydroxylase (TH) and increased glial fibrillary acidic protein (GFAP) levels in the striatum. Both treatments with magnolol significantly attenuated MPTP-induced decrease in DAT and TH protein levels in the striatum. However, these treatments did not affect MPTP-induced increase in GFAP levels. Moreover, oral administration of magnolol almost completely prevented MPTP-induced lipid peroxidation in the striatum. In human neuroblastoma SH-SY5Y cells, magnolol significantly attenuated MPP+-induced cytotoxicity and the production of reactive oxygen species. These results suggest that magnolol has protective effects via an antioxidative mechanism in bothin vivoandin vitromodels of Parkinson’s disease.

scholarly journals 2-Hydroxy-4-Methylbenzoic Anhydride Inhibits Neuroinflammation in Cellular and Experimental Animal Models of Parkinson’s Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8195
Author(s):  
Soo-Yeol Song ◽  
In-Su Kim ◽  
Sushruta Koppula ◽  
Ju-Young Park ◽  
Byung-Wook Kim ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Parent Compound ◽  
Intraperitoneal Administration ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Protein Levels

Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson’s disease (PD). In vitro studies revealed that HMA significantly inhibited lipopolysaccharide (LPS)-stimulated excessive release of nitric oxide (NO) in a concentration dependent manner. In addition, HMA significantly suppressed both inducible NO synthase and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in LPS-stimulated BV-2 microglia cells. Moreover, HMA significantly inhibited the proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in LPS-stimulated BV-2 microglial cells. Furthermore, mechanistic studies ensured that the potent anti-neuroinflammatory effects of HMA (0.1, 1.0, and 10 μM) were mediated by phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) in LPS-stimulated BV-2 cells. In vivo evaluations revealed that intraperitoneal administration of potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg, four times a 1 day) in mice resulted in activation of microglia in the brain in association with severe behavioral deficits as assessed using a pole test. However, prevention of microglial activation and attenuation of Parkinson’s disease (PD)-like behavioral changes was obtained by oral administration of HMA (30 mg/kg) for 14 days. Considering the overall results, our study showed that HMA exhibited strong anti-neuroinflammatory effects at lower concentrations than its parent compound. Further work is warranted in other animal and genetic models of PD for evaluating the efficacy of HMA to develop a potential therapeutic agent in the treatment of microglia-mediated neuroinflammatory disorders, including PD.

scholarly journals Functional amyloids in the microbiomes of a rat Parkinson's disease model and wild-type rats

2021 ◽  
Author(s):  
Line F Christensen ◽  
Saeid H Alijanvand ◽  
Michał Burdukiewicz ◽  
Florian Alexander Herbst ◽  
Henrik Kjeldal ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Formic Acid ◽  
Proteinase K ◽  
Amyloid Formation ◽  
Wild Type ◽  
Amyloid Proteins ◽  
Fecal Matter ◽  
Functional Amyloid

Cross-seeding between amyloidogenic proteins in the gut is receiving increasing attention as a possible mechanism for initiation or acceleration of amyloid formation by aggregation-prone proteins such as αSN, which is central in the development of Parkinson's disease. This is particularly pertinent in view of the growing number of functional (i.e. benign and useful) amyloid proteins discovered in bacteria. Here we identify two functional amyloid proteins, Pr12 and Pr17, in fecal matter from Parkinson's disease transgenic rats and their wild type counterparts, based on their stability against dissolution by formic acid. Both proteins show robust aggregation into ThT-positive aggregates that contain higher-order b-sheets and have a fibrillar morphology, indicative of amyloid proteins. In addition, Pr17 aggregates formed in vitro showed significant resistance against formic acid, suggesting an ability to form highly stable amyloid. Treatment with proteinase K revealed a protected core of approx. 9 kDa. Neither Pr12 nor Pr17, however, affected αSN aggregation in vitro. Thus, amyloidogenicity does not per se lead to an ability to cross-seed fibrillation of αSN. Our results support the use of proteomics and formic acid to identify amyloid protein in complex mixtures and indicates the existence of numerous functional amyloid proteins in microbiomes.

scholarly journals The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yunpeng Sun ◽  
Houfang Long ◽  
Wencheng Xia ◽  
Kun Wang ◽  
Xia Zhang ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Strain Selection ◽  
Wild Type ◽  
Distinct Structure ◽  
The Cross ◽  
Familial Parkinson’S Disease ◽  
Selection Of

Abstractα-Synuclein (α-Syn) can form different fibril strains with distinct polymorphs and neuropathologies, which is associated with the clinicopathological variability in synucleinopathies. How different α-syn fibril strains are produced and selected under disease conditions remains poorly understood. In this study, we show that the hereditary mutation G51D induces α-syn to form a distinct fibril strain in vitro. The cryogenic electron microscopy (cryo-EM) structure of the G51D fibril strain was determined at 2.96 Å resolution. The G51D fibril displays a relatively small and extended serpentine fold distinct from other α-syn fibril structures. Moreover, we show by cryo-EM that wild-type (WT) α-syn can assembly into the G51D fibril strain via cross-seeding with G51D fibrils. Our study reveals a distinct structure of G51D fibril strain triggered by G51D mutation but feasibly adopted by both WT and G51D α-syn, which suggests the cross-seeding and strain selection of WT and mutant α-syn in familial Parkinson’s disease (fPD).

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