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parkinson's disease and autophagy

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https://www.readbyqxmd.com/read/28431223/pink1-based-screen-shines-light-on-autophagy-enhancers-for-parkinson-s-disease
#1
Dominik Haddad, Ken Nakamura
In this issue of Cell Chemical Biology, Zhang et al. (2017) report a zebrafish model of Parkinson's disease (PD), incorporating the PD-protein PINK1 and rotenone, a toxin linked to PD. Using it as a drug-screening platform, they identify trifluoperazine and other piperazine phenothiazines as protective compounds that enhance autophagy independent of PINK1.
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28428740/protein-quality-control-by-molecular-chaperones-in-neurodegeneration
#2
REVIEW
Aaron Ciechanover, Yong Tae Kwon
Protein homeostasis (proteostasis) requires the timely degradation of misfolded proteins and their aggregates by protein quality control (PQC), of which molecular chaperones are an essential component. Compared with other cell types, PQC in neurons is particularly challenging because they have a unique cellular structure with long extensions. Making it worse, neurons are postmitotic, i.e., cannot dilute toxic substances by division, and, thus, are highly sensitive to misfolded proteins, especially as they age...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28400718/rab-gtpases-the-key-players-in-the-molecular-pathway-of-parkinson-s-disease
#3
REVIEW
Meng-Meng Shi, Chang-He Shi, Yu-Ming Xu
Parkinson's disease (PD) is a progressive movement disorder with multiple non-motor symptoms. Although family genetic mutations only account for a small proportion of the cases, these mutations have provided several lines of evidence for the pathogenesis of PD, such as mitochondrial dysfunction, protein misfolding and aggregation, and the impaired autophagy-lysosome system. Recently, vesicle trafficking defect has emerged as a potential pathogenesis underlying this disease. Rab GTPases, serving as the core regulators of cellular membrane dynamics, may play an important role in the molecular pathway of PD through the complex interplay with numerous factors and PD-related genes...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28390981/neurochemical-effects-of-the-r-form-of-%C3%AE-lipoic-acid-and-its-neuroprotective-mechanism-in-cellular-models-of-parkinson-s-disease
#4
Hong Zhao, Xingcheng Zhao, Lijuan Liu, Hongxu Zhang, Mingwen Xuan, Zhaohui Guo, Hongcai Wang, Chang Liu
OBJECTIVE: Parkinson's disease (PD) is a common neurodegenerative disease. This study aimed to investigate the effects of the R form of α-lipoic acid (RLA) in cellular models of PD induced by 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). METHODS: Cell viability and apoptosis were detected using CCK8 and Annexin V-FITC assays, respectively. Intracellular reactive oxygen species (ROS) were detected by fluorescence staining. ELISA assays were performed to detect the levels of dopamine and α-synuclein...
April 6, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28368777/pink1-and-becn1-relocalize-at-mitochondria-associated-membranes-during-mitophagy-and-promote-er-mitochondria-tethering-and-autophagosome-formation
#5
Vania Gelmetti, Priscilla De Rosa, Liliana Torosantucci, Elettra Sara Marini, Alessandra Romagnoli, Martina Di Rienzo, Giuseppe Arena, Domenico Vignone, Gian Maria Fimia, Enza Maria Valente
Mitophagy is a highly specialized process to remove dysfunctional or superfluous mitochondria through the macroautophagy/autophagy pathway, aimed at protecting cells from the damage of disordered mitochondrial metabolism and apoptosis induction. PINK1, a neuroprotective protein mutated in autosomal recessive Parkinson disease, has been implicated in the activation of mitophagy by selectively accumulating on depolarized mitochondria, and promoting PARK2/Parkin translocation to them. While these steps have been characterized in depth, less is known about the process and site of autophagosome formation upon mitophagic stimuli...
April 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28366621/rescue-of-pink1-deficiency-by-stress-dependent-activation-of-autophagy
#6
Yuxi Zhang, David T Nguyen, Ellen M Olzomer, Gin P Poon, Nicholas J Cole, Anita Puvanendran, Brigitte R Phillips, Daniel Hesselson
Stimulating autophagy is a promising therapeutic strategy for slowing the progression of neurodegenerative disease. Neurons are insensitive to current approaches based on mTOR inhibition for activating autophagy, and instead may rely on the Parkinson's disease-associated proteins PINK1 and PARKIN to activate the autophagy-lysosomal pathway in response to mitochondrial damage. We developed a multifactorial zebrafish drug-screening platform combining Pink1 deficiency with an environmental toxin to compromise mitochondrial function and trigger dopaminergic neuron loss...
April 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28365714/microrna-181a-regulates-apoptosis-and-autophagy-process-in-parkinson-s-disease-by-inhibiting-p38-mitogen-activated-protein-kinase-mapk-c-jun-n-terminal-kinases-jnk-signaling-pathways
#7
Ying Liu, Yanfeng Song, Xiaotun Zhu
BACKGROUND microRNA (miR)-181a has been reported to be downregulated in Parkinson's disease (PD), but the regulatory mechanism of miR-181a on neuron apoptosis and autophagy is still poorly understood. We aimed to investigate the neuroprotective effects of miR-181a on PD in vitro. MATERIAL AND METHODS Human SK-N-SH neuroblastoma cells were incubated with different concentrations of 1-methyl-4-phenylpyridinium ion (MPP+) to induce the PD model. The expression of miR-181a was then analyzed. After transfection with miR-181a mimic or scramble following MPP+ treatment, the expression of autophagy protein markers (LC3II, LC3I, and Beclin 1) and p38 mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinases (JNK) signaling proteins (p-p38, p38, p-JNK, and JNK) and cell apoptosis were detected...
April 2, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28361482/induction-of-pink1-parkin-mediated-mitophagy
#8
Shigeto Sato, Norihiko Furuya
PINK1/Parkin mitophagy is a key mechanism to contribute mitochondrial quality control, and the defects are thought to be a cause of those Parkinson's disease onsets. Upon loss of mitochondrial membrane potential, PINK1 and Parkin are activated to promote the proteasomal degradation of mitochondrial outer membrane proteins and selective elimination of damaged mitochondria by autophagy. In this chapter, we describe the methods for induction of PINK1/Parkin-mediated mitophagy in tissue culture cell lines.
March 31, 2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28357809/neuroprotective-effects-of-temsirolimus-in-animal-models-of-parkinson-s-disease
#9
Rosalba Siracusa, Irene Paterniti, Marika Cordaro, Rosalia Crupi, Giuseppe Bruschetta, Michela Campolo, Salvatore Cuzzocrea, Emanuela Esposito
Parkinson's disease (PD) is a disorder caused by degeneration of dopaminergic neurons. At the moment, there is no cure. Recent studies have shown that autophagy may have a protective function against the advance of a number of neurodegenerative diseases. Temsirolimus is an analogue of rapamycin that induces autophagy by inhibiting mammalian target of rapamycin complex 1. For this purpose, in the present study we investigated the neuroprotective effects of temsirolimus (5 mg/kg intraperitoneal) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced (MPTP) neurotoxicity in in vivo model of PD...
March 29, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28353287/mechanisms-of-mutant-lrrk2-neurodegeneration
#10
Mark R Cookson
LRRK2 mutations are associated with the loss of neurons, that is to say toxicity, in patients and in experimental model systems. However, the mechanisms by which mutations can be linked to neurodegeneration are not fully defined. Here I will argue that mechanism in this context encompasses a variety of levels of information. Mutations or alterations in gene expression at a genetic level are one set of mechanisms that are reflected at the biochemical level likely in enhanced or persistent function of LRRK2. By impacting cellular pathways, prominently including changes in autophagy but also microtubule function, mitochondria and protein synthesis, in neurons and immune cells, the LRRK2 brain is primed for neurodegeneration in an age-dependent manner...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353286/interaction-of-lrrk2-and-%C3%AE-synuclein-in-parkinson-s-disease
#11
João Paulo Lima Daher
Parkinson's disease (PD) is a progressively debilitating neurodegenerative syndrome. It is best described as a movement disorder characterized by motor dysfunctions, progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, and abnormal intraneuronal protein aggregates, named Lewy bodies and Lewy neurites. Nevertheless, knowledge of the molecular events leading to this pathophysiology is incomplete. To date, only mutations in the α-synuclein and LRRK2-encoding genes have been associated with typical findings of clinical and pathologic PD...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353282/lrrk2-and-the-immune-system
#12
Nicolas L Dzamko
Polymorphisms in leucine-rich repeat kinase 2 (LRRK2) have been linked to familial Parkinson's disease, increased risk of sporadic Parkinson's disease, increased risk of Crohn's inflammatory bowel disease, and increased susceptibility to leprosy. As well as LRRK2 mutations, these diseases share in common immune dysfunction and inflammation. LRRK2 is highly expressed in particular immune cells and has been biochemically linked to the intertwined pathways regulating inflammation, mitochondrial function, and autophagy/lysosomal function...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353280/lrrk2-and-autophagy
#13
Claudia Manzoni, Patrick A Lewis
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in a wide range of cellular processes, including the catabolic pathways collectively described as autophagy. In this chapter, the evidence linking LRRK2 to autophagy will be examined, along with how regulation of autophagy and lysosomal pathways may provide a nexus between the physiological function of this protein and the different diseases with which it has been associated. Data from cellular and animal models for LRRK2 function and dysfunction support a role in the regulation and control of autophagic pathways in the cell, although the extant results do not provide a clear indication as to whether LRRK2 is a positive or negative regulator of these pathways, and there are conflicting data as to the impact of mutations in LRRK2 causative for Parkinson's disease...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28350199/a-novel-autophagy-modulator-6-bio-ameliorates-snca-%C3%AE-synuclein-toxicity
#14
S N Suresh, Aravinda K Chavalmane, Vidyadhara D J, Haorei Yarreiphang, Shashank Rai, Abhik Paul, James P Clement, Phalguni Anand Alladi, Ravi Manjithaya
Parkinson disease (PD) is a life-threatening neurodegenerative movement disorder with unmet therapeutic intervention. We have identified a small molecule autophagy modulator, 6-Bio that shows clearance of toxic SNCA/α-synuclein (a protein implicated in synucleopathies) aggregates in yeast and mammalian cell lines. 6-Bio induces autophagy and dramatically enhances autolysosome formation resulting in SNCA degradation. Importantly, neuroprotective function of 6-Bio as envisaged by immunohistology and behavior analyses in a preclinical model of PD where it induces autophagy in dopaminergic neurons of mice midbrain to clear toxic protein aggregates suggesting that it could be a potential therapeutic candidate for protein conformational disorders...
March 28, 2017: Autophagy
https://www.readbyqxmd.com/read/28338241/neuroprotective-effects-of-loganin-on-mptp-induced-parkinson-s-disease-mice-neurochemistry-glial-reaction-and-autophagy-studies
#15
Yi-Da Xu, Chun Cui, Meng-Fei Sun, Ying-Li Zhu, Min Chu, Yun-Wei Shi, Stanley Li Lin, Xu-Sheng Yang, Yan-Qin Shen
Parkinson's disease (PD) is a progressive neurodegenerative disease, involving resting tremor and bradykinesia, for which no recognized therapies or drugs are available to halt or slow progression. In recent years, natural botanic products have been considered relatively safe, with limited side effects, and are expected to become an important source for clinical mediation of PD in the future. Our study focuses on the ability of loganin, a compound derived from fruits of cornus, to mediate neuroprotection in a mouse model of PD...
March 24, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28337125/neuronal-mitophagy-in-neurodegenerative-diseases
#16
REVIEW
Marta Martinez-Vicente
Neuronal homeostasis depends on the proper functioning of different quality control systems. All intracellular components are subjected to continuous turnover through the coordinated synthesis, degradation and recycling of their constituent elements. Autophagy is the catabolic mechanism by which intracellular cytosolic components, including proteins, organelles, aggregates and any other intracellular materials, are delivered to lysosomes for degradation. Among the different types of selective autophagy described to date, the process of mitophagy involves the selective autophagic degradation of mitochondria...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28331029/the-sac1-domain-in-synaptojanin-is-required-for%C3%A2-autophagosome-maturation-at-presynaptic%C3%A2-terminals
#17
Roeland Vanhauwaert, Sabine Kuenen, Roy Masius, Adekunle Bademosi, Julia Manetsberger, Nils Schoovaerts, Laura Bounti, Serguei Gontcharenko, Jef Swerts, Sven Vilain, Marina Picillo, Paolo Barone, Shashini T Munshi, Femke Ms de Vrij, Steven A Kushner, Natalia V Gounko, Wim Mandemakers, Vincenzo Bonifati, Frederic A Meunier, Sandra-Fausia Soukup, Patrik Verstreken
Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinson's disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P2, but this function appears normal in Synaptojanin(RQ) knock-in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P2, two lipids found in autophagosomal membranes...
March 22, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28282924/autophagy-and-microglia-novel-partners-in-neurodegeneration-and-aging
#18
REVIEW
Ainhoa Plaza-Zabala, Virginia Sierra-Torre, Amanda Sierra
Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases...
March 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28282269/endoa-endophilin-a-creates-docking-stations-for-autophagic-proteins-at-synapses
#19
Sandra-Fausia Soukup, Patrik Verstreken
Synapses are very specialized compartments with high metabolic demand to maintain neurotransmission, an essential step for basic brain function. Neurons are post-mitotic and synapses need to stay functional over time-sometimes over decades. Given that synapses are often at a long distance from the cell body, they must use local mechanisms to regulate protein quality control. We show that macroautophagy/autophagy is one of these local processes and found that it is under strict control of the synapse-enriched protein EndoA/Endophilin-A, previously only implicated in endocytosis...
February 15, 2017: Autophagy
https://www.readbyqxmd.com/read/28279708/genetic-analysis-of-the-atg16l1-gene-promoter-in-sporadic-parkinson-s-disease
#20
Lixia Wang, Jian Huang, Shuchao Pang, Xianyun Qin, Ziyou Qi, Robert G Hawley, Bo Yan
Parkinson's disease (PD) is a common and progressive neurodegenerative disease in which the majority of cases arise sporadically. Sporadic PD is caused by the interactions of genetic and environmental factors. To date, genetic causes for sporadic PD remain largely unknown. Autophagy, a highly conserved cellular process, has been implicated in PD pathogenesis. We speculated that genetic variants in autophagy-related genes (ATG) that regulate gene expression may contribute to PD development. In our previous studies, we have identified several functional DNA sequence variants (DSVs) in the ATG5, ATG7 and LC3 genes in sporadic PD patients...
March 6, 2017: Neuroscience Letters
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