Regulation of sub-compartmental targeting and folding properties of the Prion-like protein Shadoo

Pepe, Anna; Avolio, Rosario; Matassa, Danilo Swann; Esposito, Franca; Nitsch, Lucio; Zurzolo, Chiara; Paladino, Simona; Sarnataro, Daniela

doi:10.1038/s41598-017-03969-2

Cited by 16 publications

(35 citation statements)

References 56 publications

(103 reference statements)

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“…GT1 cells grown on dishes were cooled on ice and biotinylated with NHS-LC-Biotin at 4 • C (as previously indicated [57,58]. Cells were lysed for 20 min using buffer 1 (25 mM Tris-HCl pH 7.5), 150 mM NaCl, 5 mM EDTA, 1% TX-100).…”

Section: Biotinylation Assaymentioning

confidence: 99%

APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells

Bhattacharya

Limone

Napolitano

et al. 2020

IJMS

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Amyloid precursor protein (APP) is processed along both the nonamyloidogenic pathway preventing amyloid beta peptide (Aβ) production and the amyloidogenic pathway, generating Aβ, whose accumulation characterizes Alzheimer's disease. Items of evidence report that the intracellular trafficking plays a key role in the generation of Aβ and that the 37/67 kDa LR (laminin receptor), acting as a receptor for Aβ, may mediate Aβ-pathogenicity. Moreover, findings indicating interaction between the receptor and the key enzymes involved in the amyloidogenic pathway suggest a strong link between 37/67 kDa LR and APP processing. We show herein that the specific 37/67 kDa LR inhibitor, NSC48478, is able to reversibly affect the maturation of APP in a pH-dependent manner, resulting in the partial accumulation of the immature APP isoforms (unglycosylated/acetylated forms) in the endoplasmic reticulum (ER) and in transferrin-positive recycling endosomes, indicating alteration of the APP intracellular trafficking. These effects reveal NSC48478 inhibitor as a novel small molecule to be tested in disease conditions, mediated by the 37/67 kDa LR and accompanied by inactivation of ERK1/2 (extracellular signal-regulated kinases) signalling and activation of Akt (serine/threonine protein kinase) with consequent inhibition of GSK3β.

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Section: Biotinylation Assaymentioning

confidence: 99%

APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells

Bhattacharya

Limone

Napolitano

et al. 2020

IJMS

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“…In vitro experiments with amyloid fibrils and artificial membrane matrices show that lipid‐fibril interactions can affect formation of biological membranes . It has been recently reported that Shadoo (Sho), a partially proteinase K (PK)‐resistant and aggregation prone member of prion protein family, associates with lipid rafts and some of it can be found to localize at the ER . Therefore, it will be interesting to see how cytosolic aggregates can affect lipid composition of different endomembranes and how this is affected by the presence of non‐translocated proteins.…”

Section: Discussionmentioning

confidence: 99%

Cytosolic aggregates in presence of non‐translocated proteins perturb endoplasmic reticulum structure and dynamics

Mookherjee

Majumder

Mukherjee

et al. 2019

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Presence of cytosolic protein aggregates and membrane damage are two common attributes of neurodegenerative diseases. These aggregates delay degradation of non‐translocated protein precursors leading to their persistence and accumulation in the cytosol. Here, we find that cells with intracellular protein aggregates (of cytosolic prion protein or huntingtin) destabilize the endoplasmic reticulum (ER) morphology and dynamics when non‐translocated protein load is high. This affects trafficking of proteins out from the ER, relative distribution of the rough and smooth ER and three‐way junctions that are essential for the structural integrity of the membrane network. The changes in ER membranes may be due to high aggregation tendency of the ER structural proteins—reticulons, and altered distribution of those associated with the three‐way ER junctions—Lunapark. Reticulon4 is seen to be enriched in the aggregate fractions in presence of non‐translocated protein precursors. This could be mitigated by improving signal sequence efficiencies of the proteins targeted to the ER. These were observed using PrP variants and the seven‐pass transmembrane protein (CRFR1) with different signal sequences that led to diverse translocation efficiencies. This identifies a previously unappreciated consequence of cytosolic aggregates on non‐translocated precursor proteins—their persistent presence affects ER morphology and dynamics. This may be one of the ways in which cytosolic aggregates can affect endomembranes during neurodegenerative disease.

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“…Although various misfolded GPI-APs accumulate after proteasome inhibitor treatment, suggesting that the ERAD is involved in their turnover [ 6 , 13 , 21 , 22 ], it has been reported that misfolded GPI-anchored proteins do not pass through the canonical ERAD pathway but seem to be targeted to the alternative ER stress-induced pathway called RESET [ 23 ]. Thanks to RESET, misfolded GPI-APs dissociate from resident ER chaperones, leaving the ER and accessing the cell surface transiently before degradation in lysosomes ( Figure 1 B).…”

Section: Er/golgi Quality Control and The Role Of Gpi-anchor In Prmentioning

confidence: 99%

Attempt to Untangle the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases

Sarnataro

2018

IJMS

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The misfolding and aggregation of proteins is the neuropathological hallmark for numerous diseases including Alzheimer’s disease, Parkinson’s disease, and prion diseases. It is believed that misfolded and abnormal β-sheets forms of wild-type proteins are the vectors of these diseases by acting as seeds for the aggregation of endogenous proteins. Cellular prion protein (PrPC) is a glycosyl-phosphatidyl-inositol (GPI) anchored glycoprotein that is able to misfold to a pathogenic isoform PrPSc, the causative agent of prion diseases which present as sporadic, dominantly inherited and transmissible infectious disorders. Increasing evidence highlights the importance of prion-like seeding as a mechanism for pathological spread in Alzheimer’s disease and Tauopathy, as well as other neurodegenerative disorders. Here, we report the latest findings on the mechanisms controlling protein folding, focusing on the ER (Endoplasmic Reticulum) quality control of GPI-anchored proteins and describe the “prion-like” properties of amyloid-β and tau assemblies. Furthermore, we highlight the importance of pathogenic assemblies interaction with protein and lipid membrane components and their implications in both prion and Alzheimer’s diseases

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Regulation of sub-compartmental targeting and folding properties of the Prion-like protein Shadoo

Cited by 16 publications

References 56 publications

APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells

APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells

Cytosolic aggregates in presence of non‐translocated proteins perturb endoplasmic reticulum structure and dynamics

Attempt to Untangle the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases

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