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Prion and autophagy

Shambhunath Bose, Jungsook Cho
Protein misfolding, which is known to cause several serious diseases, is an emerging field that addresses multiple therapeutic areas. Misfolding of a disease-specific protein in the central nervous system ultimately results in the formation of toxic aggregates that may accumulate in the brain, leading to neuronal cell death and dysfunction, and associated clinical manifestations. A large number of neurodegenerative diseases in humans, including Alzheimer's, Parkinson's, Huntington's, and prion diseases, are primarily caused by protein misfolding and aggregation...
October 1, 2016: Ageing Research Reviews
Rajesh Kumar, Peter P Nawroth, Jens Tyedmers
Aggregation of amyloidogenic proteins is associated with several neurodegenerative diseases. Sequestration of misfolded and aggregated proteins into specialized deposition sites may reduce their potentially detrimental properties. Yeast exhibits a distinct deposition site for amyloid aggregates termed "Insoluble PrOtein Deposit (IPOD)", but nothing is known about the mechanism of substrate recruitment to this site. The IPOD is located directly adjacent to the Phagophore Assembly Site (PAS) where the cell initiates autophagy and the Cytoplasm-to-Vacuole Targeting (CVT) pathway destined for delivery of precursor peptidases to the vacuole...
September 2016: PLoS Genetics
Marcos V S Dias, Bianca L Teixeira, Bruna R Rodrigues, Rita Sinigaglia-Coimbra, Isabel Porto-Carreiro, Martín Roffé, Glaucia N M Hajj, Vilma R Martins
Prion protein modulates many cellular functions including the secretion of trophic factors by astrocytes. Some of these factors are found in exosomes, which are formed within multivesicular bodies (MVBs) and secreted into the extracellular space to modulate cell-cell communication. The mechanisms underlying exosome biogenesis were not completely deciphered. Here, we demonstrate that primary cultures of astrocytes and fibroblasts from prnp-null mice secreted lower levels of exosomes than wild-type cells. Furthermore, prnp-null astrocytes exhibited reduced MVB formation and increased autophagosome formation...
September 14, 2016: Autophagy
Sher Hayat Khan, Deming Zhao, Syed Zahid Ali Shah, Mohammad Farooque Hassan, Ting Zhu, Zhiqi Song, Xiangmei Zhou, Lifeng Yang
Transmissible spongiform encephalopathies (TSEs) are caused by the accumulation of the abnormal prion protein scrapie (PrP(Sc)). Prion protein aggregation, misfolding, and cytotoxicity in the brain are the major causes of neuronal dysfunction and ultimate neurodegeneration in all TSEs. Parkin, an E3 ubiquitin ligase, has been studied extensively in all major protein misfolding aggregating diseases, especially Parkinson's disease and Alzheimer's disease, but the role of parkin in TSEs remains unknown. Here we investigated the role of parkin in a prion disease cell model in which neuroblastoma2a (N2a) cells were treated with prion peptide PrP106-126...
July 18, 2016: Cellular and Molecular Neurobiology
Aram B Cholanians, Andy V Phan, Eric J Ditzel, Todd D Camenisch, Serrine S Lau, Terrence J Monks
Synucleinopathies, including Parkinson's disease (PD), are neurodegenerative diseases characterized by accumulation of α-synuclein (SYN), a small neuronal protein with prion like properties that plays a central role in PD pathogenesis. SYN can misfold and generate toxic oligomers/aggregates, which can be cytotoxic. Environmental arsenic (As)-containing pesticide use correlates with increased incidence of PD. Moreover, because As exposure can lead to inhibition of autophagic flux we hypothesize that As can facilitate the accumulation of toxic SYN oligomers/aggregates and subsequent increases in markers of autophagy...
October 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Hui Wang, Chan Tian, Jing Sun, Li-Na Chen, Yan Lv, Xiao-Dong Yang, Kang Xiao, Jing Wang, Cao Chen, Qi Shi, Qi-Xiang Shao, Xiao-Ping Dong
Polo-like kinase 3 (PLK3) is the main cause of cell cycle reentry-related neuronal apoptosis which has been implicated in the pathogenesis of prion diseases. Previous work also showed the regulatory activity of exogenous PLK3 on the degradation of PrP (prion protein) mutants and pathogenic PrP(Sc); however, the precise mechanisms remain unknown. In this study, we identified that the overexpression of PLK3-mediated degradation of PrP mutant and PrP(Sc) was repressed by lysosome rather than by proteasomal and macroautophagy inhibitors...
June 25, 2016: Molecular Neurobiology
Zachary Monahan, Frank Shewmaker, Udai Bhan Pandey
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease caused by loss of upper and lower motor neurons. The majority of ALS cases are classified as sporadic (80-90%), with the remaining considered familial based on patient history. The last decade has seen a surge in the identification of ALS-causing genes - including TARDBP (TDP-43), FUS, MATR3 (Matrin-3), C9ORF72 and several others - providing important insights into the molecular pathways involved in pathogenesis. Most of the protein products of ALS-linked genes fall into two functional categories: RNA-binding/homeostasis and protein-quality control (i...
May 13, 2016: Brain Research
Yin Xu, Heidi Martini-Stoica, Hui Zheng
BACKGROUND: Tauopathy is characterized by neurofibrillary tangles composed of insoluble hyperphosphorylated tau protein. Currently, cellular models that mimic neurofibrillary tangles in vitro are lacking. Previous studies indicate that neurofibrillary tangles form via a prion replication mechanism. In the present work, we establish a seeding based cellular model according to the prion hypothesis. RESULTS: We show that cellular soluble tau can be converted to insoluble tau by seeds from the brain lysate of rTg4510 mice or synthetically generated preformed tau fibrils (PFFs)...
2016: Molecular Neurodegeneration
Ji-Hong Moon, Ju-Hee Lee, Uddin Md Nazim, You-Jin Lee, Jae-Won Seol, Seong-Kug Eo, John-Hwa Lee, Sang-Youel Park
An unusual molecular structure of the prion protein, PrPsc is found only in mammals with transmissible prion diseases. Prion protein stands for either the infectious pathogen itself or a main component of it. Recent studies suggest that autophagy is one of the major functions that keep cells alive and has a protective effect against the neurodegeneration. In this study, we investigated that the effect of human prion protein on autophagy-lysosomal system of primary neuronal cells. The treatment of human prion protein induced primary neuron cell death and decreased both LC3-II and p62 protein amount indicating autophagy flux activation...
May 24, 2016: Oncotarget
Ji-Hong Moon, Ju-Hee Lee, You-Jin Lee, Sang-Youel Park
Prion diseases are fatal neurodegenerative disorders that are derived from structural changes of the native PrPc. Recent studies indicated that hinokitiol induced autophagy known to major function that keeps cells alive under stressful conditions. We investigated whether hinokitiol induces autophagy and attenuates PrP (106-126)-induced neurotoxicity. We observed increase of LC3-II protein level, GFP-LC3 puncta by hinokitiol in neuronal cells. Addition to, electron microscopy showed that hinokitiol enhanced autophagic vacuoles in neuronal cells...
May 24, 2016: Oncotarget
Kundlik Gadhave, Nityanand Bolshette, Ashutosh Ahire, Rohit Pardeshi, Krishan Thakur, Cristiana Trandafir, Alexandru Istrate, Sahabuddin Ahmed, Mangala Lahkar, Dafin F Muresanu, Maria Balea
The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age-related neurodegenerative diseases...
July 2016: Journal of Cellular and Molecular Medicine
Heidi Martini-Stoica, Yin Xu, Andrea Ballabio, Hui Zheng
The autophagy-lysosomal pathway (ALP) is involved in the degradation of long-lived proteins. Deficits in the ALP result in protein aggregation, the generation of toxic protein species, and accumulation of dysfunctional organelles, which are hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and prion disease. Decades of research have therefore focused on enhancing the ALP in neurodegenerative diseases. More recently, transcription factor EB (TFEB), a major regulator of autophagy and lysosomal biogenesis, has emerged as a leading factor in addressing disease pathology...
April 2016: Trends in Neurosciences
Yu Cai, Jyothi Arikkath, Lu Yang, Ming-Lei Guo, Palsamy Periyasamy, Shilpa Buch
The common underlying feature of most neurodegenerative diseases such as Alzheimer disease (AD), prion diseases, Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) involves accumulation of misfolded proteins leading to initiation of endoplasmic reticulum (ER) stress and stimulation of the unfolded protein response (UPR). Additionally, ER stress more recently has been implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Autophagy plays an essential role in the clearance of aggregated toxic proteins and degradation of the damaged organelles...
2016: Autophagy
Pawel Stocki, Maxime Sawicki, Charles E Mays, Seo Jung Hong, Daniel C Chapman, David Westaway, David B Williams
Prion diseases are fatal neurodegenerative disorders for which there is no effective treatment. Because the cellular prion protein (PrP(C)) is required for propagation of the infectious scrapie form of the protein, one therapeutic strategy is to reduce PrP(C) expression. Recently FK506, an inhibitor of the FKBP family of peptidyl prolyl isomerases, was shown to increase survival in animal models of prion disease, with proposed mechanisms including calcineurin inhibition, induction of autophagy, and reduced PrP(C) expression...
March 1, 2016: Molecular Biology of the Cell
Lorna Moll, Tziona Ben-Gedalya, Hadas Reuveni, Ehud Cohen
The discovery that the alteration of aging by reducing the activity of the insulin/IGF-1 signaling (IIS) cascade protects nematodes and mice from neurodegeneration-linked, toxic protein aggregation (proteotoxicity) raises the prospect that IIS inhibitors bear therapeutic potential to counter neurodegenerative diseases. Recently, we reported that NT219, a highly efficient IGF-1 signaling inhibitor, protects model worms from the aggregation of amyloid β peptide and polyglutamine peptides that are linked to the manifestation of Alzheimer's and Huntington's diseases, respectively...
April 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Irina Milisav, Dušan Šuput, Samo Ribarič
Proteostasis are integrated biological pathways within cells that control synthesis, folding, trafficking and degradation of proteins. The absence of cell division makes brain proteostasis susceptible to age-related changes and neurodegeneration. Two key processes involved in sustaining normal brain proteostasis are the unfolded protein response and autophagy. Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases (PrDs) have different clinical manifestations of neurodegeneration, however, all share an accumulation of misfolded pathological proteins associated with perturbations in unfolded protein response and macroautophagy...
2015: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
P Majumder, O Chakrabarti
Aberrant metabolic forms of the prion protein (PrP), membrane-associated (Ctm)PrP and cytosolic (cyPrP) interact with the cytosolic ubiquitin E3 ligase, Mahogunin Ring Finger-1 (MGRN1) and affect lysosomes. MGRN1 also interacts with and ubiquitinates TSG101, an ESCRT-I protein, involved in endocytosis. We report that MGRN1 modulates macroautophagy. In cultured cells, functional depletion of MGRN1 or overexpression of (Ctm)PrP and cyPrP blocks autophagosome-lysosome fusion, alleviates the autophagic flux and its degradative competence...
2015: Cell Death & Disease
Ting Zhu, Deming Zhao, Zhiqi Song, Zhen Yuan, Chaosi Li, Yunsheng Wang, Xiangmei Zhou, Xiaomin Yin, Muhammad Farooque Hassan, Lifeng Yang
Histone deacetylase 6 (HDAC6) controls several major cellular responses to stress that play a role in neurodegenerative diseases, including aggresome formation, autophagy, and apoptosis. However, the specific role of HDAC6 in prion diseases is not known. In this study, we examined the relationship between HDAC6 and cellular response to the neurotoxic synthetic prion protein fragment PrP106-126. We determined that exposure of cerebral cortical neurons to this fragment alters the expression and localization of HDAC6...
January 2016: Neurobiology of Aging
Shaun H Speldewinde, Victoria A Doronina, Chris M Grant
Prions are self-propagating, infectious proteins that underlie several neurodegenerative diseases. The molecular basis underlying their sporadic formation is poorly understood. We show that autophagy protects against de novo formation of [PSI(+)], which is the prion form of the yeast Sup35 translation termination factor. Autophagy is a cellular degradation system, and preventing autophagy by mutating its core components elevates the frequency of spontaneous [PSI(+)] formation. Conversely, increasing autophagic flux by treating cells with the polyamine spermidine suppresses prion formation in mutants that normally show a high frequency of de novo prion formation...
December 15, 2015: Molecular Biology of the Cell
Xue-Yu Fan, Chan Tian, Hui Wang, Yin Xu, Ke Ren, Bao-Yun Zhang, Chen Gao, Qi Shi, Ge Meng, Lu-Bin Zhang, Yang-Jing Zhao, Qi-Xiang Shao, Xiao-Ping Dong
AMPK is a serine/threonine protein kinase that acts as a positive regulator of autophagy, by phosphorylating ULK1 at specific sites. A previous study demonstrated activation of the macroautophagic system in scrapie-infected experimental rodents and in certain human prion diseases, in which the essential negative regulator mTOR is severely inhibited. In this study, AMPK and ULK1 in the brains of hamsters infected with scrapie strain 263 K and in the scrapie-infected cell line SMB-S15 were analysed. The results showed an up-regulated trend of AMPK and AMPK-Thr172, ULK1 and ULK1-Ser555...
2015: Scientific Reports
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