Article

Functional Depletion of Mahogunin by Cytosolically Exposed Prion Protein Contributes to Neurodegeneration

Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Cell (Impact Factor: 32.24). 07/2009; 137(6):1136-47. DOI: 10.1016/j.cell.2009.03.042
Source: PubMed

ABSTRACT

The pathways leading from aberrant Prion protein (PrP) metabolism to neurodegeneration are poorly understood. Some familial PrP mutants generate increased (Ctm)PrP, a transmembrane isoform associated with disease. In other disease situations, a potentially toxic cytosolic form (termed cyPrP) might be produced. However, the mechanisms by which (Ctm)PrP or cyPrP cause selective neuronal dysfunction are unknown. Here, we show that both (Ctm)PrP and cyPrP can interact with and disrupt the function of Mahogunin (Mgrn), a cytosolic ubiquitin ligase whose loss causes spongiform neurodegeneration. Cultured cells and transgenic mice expressing either (Ctm)PrP-producing mutants or cyPrP partially phenocopy Mgrn depletion, displaying aberrant lysosomal morphology and loss of Mgrn in selected brain regions. These effects were rescued by either Mgrn overexpression, competition for PrP-binding sites, or prevention of cytosolic PrP exposure. Thus, transient or partial exposure of PrP to the cytosol leads to inappropriate Mgrn sequestration that contributes to neuronal dysfunction and disease.

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    • "Recently it has also been demonstrated that MGRN1 interacts with transmembrane ( Ctm PrP) and toxic (cyPrP) prion disease proteins; depletion of MGRN1 affects lysosomal morphology and leads to neurodegeneration likely due to such improper sequestration (Chakrabarti and Hegde, 2009). MGRN1 interacts with several proteins such as expanded polyglutamine proteins (Chhangani et al., 2014b), molecular chaperone (Chhangani and Mishra, 2013), α-tubulin (Srivastava and Chakrabarti, 2014), MC1R/MC2R (Cooray et al., 2011; Perez-Oliva et al., 2009), cyPrP/ Ctm PrP (Chakrabarti and Hegde, 2009), TSG 101 (Kim et al., 2007), and NEDD4 (Gunn et al., 2013). Under such crucial biological interactions it is plausible that a loss of function or depletion of MGRN1 can cause multifactorial defects in cells and generate various pathological states in important physiological events. "
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    ABSTRACT: Proteotoxicity of misfolded, disease-causing proteins is deeply implicated in the pathomechanisms for neurodegenerative diseases including copper-zinc superoxide dismutase (SOD1)-linked amyotrophic lateral sclerosis (ALS). However, the precise cellular quality control (QC) mechanisms against aggregation of misfolded mutant SOD1 proteins remain elusive. Here, we found that the Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase, which catalyzes mono-ubiquitination to the substrate, was dysregulated in the cellular and mouse models of ALS and that it preferentially interacted with various mutant forms of SOD1. Intriguingly, the motor neurons of presymptomatic ALS mice have diminished MGRN1 cytoplasmic distribution. MGRN1 was partially recruited to mutant SOD1 inclusions where they were positive for p62 and Lamp2. Moreover, overexpression of MGRN1 reduced mutant SOD1 aggregation and alleviated its proteotoxic effects on cells. Taken together, our findings suggest that MGRN1 contributes to the clearance of toxic mutant SOD1 inclusions likely through autophagic pathway, and, most likely, the sequestration of MGRN1 sensitizes motor neurons to degeneration in the ALS mouse model. Furthermore, the present study identifies the MGRN1-mediated protein QC mechanism as a novel therapeutic target in neurodegenerative diseases.
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    • "c o m / l o c a t e / b b a m c r aggregate intracellular proteins which are not its physiological partners [rev. in [11]]. CytoPrP interacts with cytosolic proteins such as tubulin, Bcl-2 and ubiquitin ligase mahogunin, leading to loss of their functions [12] [13] [14]. These excessive or non-physiological interactions may underlay the molecular mechanism of cytoPrP neurotoxicity in TSE [rev. "
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    ABSTRACT: Prion protein (PrP) mislocalized in the cytosol has been presumed to be the toxic entity responsible for the neurodegenerative process in transmissible spongiform encephalopathies (TSE), also called prion diseases. The mechanism underlying the neurotoxicity of cytosolic PrP (cytoPrP) remains, however, unresolved. In this study we analyze toxic effects of the cell-penetrating PrP fragment, PrP1-30 - encompassing residues responsible for binding and aggregation of tubulin. We have found that intracellularly localized PrP1-30 disassembles microtubular cytoskeleton of primary neurons, which leads to the loss of neurites and, eventually, necrotic cell death. Accordingly, stabilization of microtubules by taxol reduced deleterious effects of cytosolic PrP1-30. Furthermore, we have demonstrated that decreased phosphorylation level of microtubule-associated proteins (MAPs), which also increases stability of microtubular cytoskeleton protects neurons from the toxic effects of PrP1-30. CHIR98014 and LiCl - inhibitors of glycogen synthase kinase 3 (GSK-3), a major kinase responsible for phosphorylation of MAPs, inhibited PrP1-30-induced disruption of microtubular cytoskeleton and increased viability of peptide-treated neurons. We have also shown that the N-terminal fragment of cytoPrP may cause the loss of dendritic spines. PrP1-30-induced changes at the level of spines have also been prevented by stabilization of microtubules by taxol as well as LiCl. These observations indicate that the neurotoxicty of cytoPrP is tightly linked to the disruption of microtubular cytoskeleton. Importantly, this study implies that lithium, the commonly used mood stabilizer, may be a promising therapeutic agent in TSE, particularly in case of the disease forms associated with accumulation of cytoPrP. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Biochimica et Biophysica Acta
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    • "For example, mutations in the E3 ligase Parkin occur in Autosomal recessive Parkinson's disease. An E3 ligase called Mahogunin interacts with cytosolic Prion protein and is implicated to be involved with the pathophysiology of Prion diseases [67]. In other cases, the effect on the UPS is a secondary one; that is, the protein aggregates formed overload or inhibit the proteasome. "
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    ABSTRACT: The cell has an intricate quality control system to protect its mitochondria from oxidative stress. This surveillance system is multi-tiered and comprises molecules that are present inside the mitochondria, in the cytosol, and in other organelles like the nucleus and endoplasmic reticulum. These molecules cross talk with each other and protect the mitochondria from oxidative stress. Oxidative stress is a fundamental part of early disease pathogenesis of neurodegenerative diseases. These disorders also damage the cellular quality control machinery that protects the cell against oxidative stress. This exacerbates the oxidative damage and causes extensive neuronal cell death that is characteristic of neurodegeneration.
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