scholarly journals Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles

PLoS Genetics ◽  
2021 ◽  
Vol 17 (2) ◽  
pp. e1008859
Author(s):  
Kathryn A. Jewett ◽  
Ruth E. Thomas ◽  
Chi Q. Phan ◽  
Bernice Lin ◽  
Gillian Milstein ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Disease Progression ◽  
Ectopic Expression ◽  
Lewy Bodies ◽  
Protein Composition ◽  
Extracellular Vesicle ◽  
Mutant Protein ◽  
Protein Aggregate ◽  
Ubiquitinated Proteins ◽  
Clinical Disease Progression

Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson’s disease (PD). The spread of brain protein aggregates is associated with clinical disease progression, but how this occurs remains unclear. Mutations in glucosidase, beta acid 1 (GBA), which encodes glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies and associate with faster disease progression. To explore how GBA mutations influence pathogenesis, we previously created a Drosophila model of GBA deficiency (Gba1b) that manifests neurodegeneration and accelerated protein aggregation. Proteomic analysis of Gba1b mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs from Gba1b mutants. Accordingly, we hypothesized that GBA may influence pathogenic protein aggregate spread via EVs. We found that accumulation of ubiquitinated proteins and Ref(2)P, Drosophila homologue of mammalian p62, were reduced in muscle and brain tissue of Gba1b flies by ectopic expression of wildtype GCase in muscle. Neuronal GCase expression also rescued protein aggregation both cell-autonomously in brain and non-cell-autonomously in muscle. Muscle-specific GBA expression reduced the elevated levels of EV-intrinsic proteins and Ref(2)P found in EVs from Gba1b flies. Perturbing EV biogenesis through neutral sphingomyelinase (nSMase), an enzyme important for EV release and ceramide metabolism, enhanced protein aggregation when knocked down in muscle, but did not modify Gba1b mutant protein aggregation when knocked down in neurons. Lipidomic analysis of nSMase knockdown on ceramide and glucosylceramide levels suggested that Gba1b mutant protein aggregation may depend on relative depletion of specific ceramide species often enriched in EVs. Finally, we identified ectopically expressed GCase within isolated EVs. Together, our findings suggest that GCase deficiency promotes accelerated protein aggregate spread between cells and tissues via dysregulated EVs, and EV-mediated trafficking of GCase may partially account for the reduction in aggregate spread.

P3-424: LONGITUDINAL ACCUMULATION OF β-AMYLOID ON PET IN DEMENTIA WITH LEWY BODIES AND RELATIONSHIP TO CLINICAL DISEASE PROGRESSION

2006 ◽  
Vol 14 (7S_Part_24) ◽  
pp. P1271-P1272
Author(s):  
Zuzana Nedelska ◽  
Christopher G. Schwarz ◽  
Timothy G. Lesnick ◽  
Scott A. Przybelski ◽  
Bradley F. Boeve ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Clinical Disease ◽  
Β Amyloid ◽  
Clinical Disease Progression

IC-P-019: LONGITUDINAL ACCUMULATION OF β-AMYLOID ON PET IN DEMENTIA WITH LEWY BODIES AND RELATIONSHIP TO CLINICAL DISEASE PROGRESSION

2006 ◽  
Vol 14 (7S_Part_1) ◽  
pp. P25-P25
Author(s):  
Zuzana Nedelska ◽  
Christopher G. Schwarz ◽  
Timothy G. Lesnick ◽  
Scott A. Przybelski ◽  
Bradley F. Boeve ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Clinical Disease ◽  
Β Amyloid ◽  
Clinical Disease Progression

scholarly journals Parkinson’s Disease Causative Mutation in Vps35 Disturbs Tetherin Trafficking to Cell Surfaces and Facilitates Virus Spread

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 746
Author(s):  
Yingzhuo Ding ◽  
Yan Li ◽  
Gaurav Chhetri ◽  
Xiaoxin Peng ◽  
Jing Wu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ectopic Expression ◽  
Lewy Bodies ◽  
Cell Protein ◽  
Causative Mutation ◽  
Virus Spread ◽  
Cell Surfaces ◽  
Vacuolar Protein ◽  
Hsv 1

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra, intraneuronal deposition of misfolded proteins known as Lewy bodies, and chronic neuroinflammation. PD can arise from monogenic mutations, but in most cases, the etiology is unclear. Viral infection is gaining increasing attentions as a trigger of PD. In this study, we investigated whether the PD-causative 620 aspartate (D) to asparagine (N) mutation in the vacuolar protein sorting 35 ortholog (Vps35) precipitated herpes simplex virus (HSV) infection. We observed that ectopic expression of Vps35 significantly reduced the proliferation and release of HSV-1 virions; the D620N mutation rendered Vps35 a partial loss of such inhibitory effects. Tetherin is a host cell protein capable of restricting the spread of encapsulated viruses including HSV-1 and SARS-Cov-2, both of which are implicated in the development of parkinsonism. Compared with cells overexpressing wildtype Vps35, cells expressing mutant Vps35 with D620N had less Tetherin on cell surfaces. Real-time and static cell imaging revealed that Tetherin recycled through Vps35-positive endosomes. Expression of Vps35 with D620N reduced endosomal dynamics and frequency of motile Tetherin-containing vesicles, a sign of defective production of recycling carriers. Our study suggests that the D620N mutation in Vps35 hinders Tetherin trafficking to cell surfaces and facilitates virus spread.

scholarly journals The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

2020 ◽  
pp. jbc.RA120.014415
Author(s):  
Tapas Mukherjee ◽  
Valeria Ramaglia ◽  
Mena Abdel-Nour ◽  
Athanasia A Bianchi ◽  
Jessica Tsalikis ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Lewy Bodies ◽  
Protein Aggregates ◽  
Distal Colon ◽  
Ubiquitin Proteasome System ◽  
Pathological Feature ◽  
Protein Aggregate ◽  
Sensory Afferents ◽  
Cytosolic Protein ◽  
Eif2α Kinase

Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Recently, we found that the eIF2α kinase heme-regulated inhibitory (HRI) induced a cytosolic unfolded protein response (cUPR) to prevent aggregation of innate immune signalosomes, but whether HRI acts as a general sensor of proteotoxicity in the cytosol remains unclear. Here we show that HRI controls autophagy to clear cytosolic protein aggregates when the UPS is inhibited. We further report that silencing HRI expression resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy (CASA), suggesting that HRI controls proteostasis in the cytosol at least in part through CASA. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of over-expressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement with these data, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans. Together, these results suggest that HRI contributes to a general cUPR that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

Does protein aggregation drive postmitotic tissue degeneration?

2021 ◽  
Vol 13 (577) ◽  
pp. eaax0914 ◽  
Author(s):  
Jeffery W. Kelly
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Protein Aggregation ◽  
Protein Aggregate ◽  
Tissue Degeneration ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Amyloid Diseases ◽  
Aggregate Structures

Pharmacological evidence, from clinical trials where patients with systemic amyloid diseases are treated with disease-modifying therapies, supports the notion that protein aggregation drives tissue degeneration in these disorders. The protein aggregate structures driving tissue pathology and the commonalities in etiology between these diseases and Alzheimer’s disease are under investigation.

CD133 Expression in Medullary Thyroid Cancer Cells Identifies Patients with Poor Prognosis

2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Alfonso Cordero-Barreal ◽  
Eduardo Caleiras ◽  
Evangelina López de Maturana ◽  
María Monteagudo ◽  
Ángel M Martínez-Montes ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Disease Progression ◽  
Poor Prognosis ◽  
Medullary Thyroid Cancer ◽  
Univariate Analysis ◽  
Ectopic Expression ◽  
Stem Cell Marker ◽  
Medullary Thyroid ◽  
Cd133 Expression ◽  
Patients With Poor Prognosis

Abstract Context The identification of markers able to determine medullary thyroid cancer (MTC) patients at high-risk of disease progression is critical to improve their clinical management and outcome. Previous studies have suggested that expression of the stem cell marker CD133 is associated with MTC aggressiveness. Objective To evaluate CD133 impact on disease progression in MTC and explore the regulatory mechanisms leading to the upregulation of this protein in aggressive tumors. Patients We compiled a series of 74 MTCs with associated clinical data and characterized them for mutations in RET and RAS proto-oncogenes, presumed to be related with disease clinical behavior. Results We found that CD133 immunohistochemical expression was associated with adverse clinicopathological features and predicted a reduction in time to disease progression even when only RET-mutated cases were considered in the analysis (log-rank test P < 0.003). Univariate analysis for progression-free survival revealed CD133 expression and presence of tumor emboli in peritumoral blood vessels as the most significant prognostic covariates among others such as age, gender, and prognostic stage. Multivariate analysis identified both variables as independent factors of poor prognosis (hazard ratio = 16.6 and 2; P = 0.001 and 0.010, respectively). Finally, we defined hsa-miR-30a-5p, a miRNA downregulated in aggressive MTCs, as a CD133 expression regulator. Ectopic expression of hsa-miR-30a-5p in MZ-CRC-1 (RETM918T) cells significantly reduced CD133 mRNA expression. Conclusions Our results suggest that CD133 expression may be a useful tool to identify MTC patients with poor prognosis, who may benefit from a more extensive primary surgical management and follow-up.

scholarly journals A Novel Mechanism for NF-κB-activation via IκB-aggregation: Implications for Hepatic Mallory-Denk-Body Induced Inflammation

2020 ◽  
Vol 19 (12) ◽  
pp. 1968-1985
Author(s):  
Yi Liu ◽  
Michael J. Trnka ◽  
Shenheng Guan ◽  
Doyoung Kwon ◽  
Do-Hyung Kim ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Nuclear Import ◽  
Cell Model ◽  
Protoporphyrin Ix ◽  
Zinc Protoporphyrin ◽  
Primary Hepatocytes ◽  
Protein Aggregate ◽  
Nuclear Entry ◽  
Antibody Recognition ◽  
Bona Fide

Mallory-Denk-bodies (MDBs) are hepatic protein aggregates associated with inflammation both clinically and in MDB-inducing models. Similar protein aggregation in neurodegenerative diseases also triggers inflammation and NF-κB activation. However, the precise mechanism that links protein aggregation to NF-κB-activation and inflammatory response remains unclear. Herein we find that treating primary hepatocytes with MDB-inducing agents (N-methylprotoporphyrin (NMPP), protoporphyrin IX (PPIX), or Zinc-protoporphyrin IX (ZnPP)) elicited an IκBα-loss with consequent NF-κB activation. Four known mechanisms of IκBα-loss i.e. the canonical ubiquitin-dependent proteasomal degradation (UPD), autophagic-lysosomal degradation, calpain degradation and translational inhibition, were all probed and excluded. Immunofluorescence analyses of ZnPP-treated cells coupled with 8 M urea/CHAPS-extraction revealed that this IκBα-loss was due to its sequestration along with IκBβ into insoluble aggregates, thereby releasing NF-κB. Through affinity pulldown, proximity biotinylation by antibody recognition, and other proteomic analyses, we verified that NF-κB subunit p65, which stably interacts with IκBα under normal conditions, no longer binds to it upon ZnPP-treatment. Additionally, we identified 10 proteins that interact with IκBα under baseline conditions, aggregate upon ZnPP-treatment, and maintain the interaction with IκBα after ZnPP-treatment, either by cosequestering into insoluble aggregates or through a different mechanism. Of these 10 proteins, the nucleoporins Nup153 and Nup358/RanBP2 were identified through RNA-interference, as mediators of IκBα-nuclear import. The concurrent aggregation of IκBα, NUP153, and RanBP2 upon ZnPP-treatment, synergistically precluded the nuclear entry of IκBα and its consequent binding and termination of NF-κB activation. This novel mechanism may account for the protein aggregate-induced inflammation observed in liver diseases, thus identifying novel targets for therapeutic intervention. Because of inherent commonalities this MDB cell model is a bona fide protoporphyric model, making these findings equally relevant to the liver inflammation associated with clinical protoporphyria.

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