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Reciprocal effects of alpha-synuclein aggregation and lysosomal homeostasis in synucleinopathy models

Translational Neurodegeneration 2023年第1期12卷 479-499页

作者： Alice Drobny Fanni Annamária Boros Denise Balta Susy Prieto Huarcaya Deniz Caylioglu Niyeti Qazi Julia Vandrey Yanni Schneider Jan Philipp Dobert Caleb Pitcairn Joseph Robert Mazzulli Friederike Zunke department of Molecular neurology University Hospital ErlangenFriedrich-Alexander University Erlangen-Nürnberg91054 ErlangenGermany Institute of Biochemistry Christian-Albrechts-University KielKielGermany The ken and ruth davee department of neurology Northwestern University Feinberg School of MedicineChicagoIL 60611USA.

Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of *** PD pathology the synaptic protein alpha-synuclein(αSyn)converts from a soluble monomer to oligomeric structures and insoluble amyloid *** aim of this study was to unravel the effect ofαSyn aggregates on lysosomal turnover,particularly focusing on lysosomal homeostasis and *** these enzymes have been shown to be directly involved in the lysosomal degradation ofαSyn,impairment of their enzymatic capacity has extensive *** We used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellularαSyn conformers on cell homeostasis and lysosomal function in dopaminergic(DA)neurons by biochemical *** We found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models withαSyn aggregation,resulting in reduced proteolytic activity of cathepsins in the *** a farnesyltransferase inhibitor,which boosts hydrolase transport via activation of the SNARE protein ykt6,we enhanced the maturation and proteolytic activity of cathepsins and thereby decreasedαSyn protein *** Our findings demonstrate a strong interplay betweenαSyn aggregation pathways and function of lysosomal *** appears thatαSyn directly interferes with the enzymatic function of cathepsins,which might lead to a vicious cycle of impairedαSyn degradation.

关键词： Dopaminergic neurons iPSC-derived models Lysosome Parkinson’s disease Protein trafficking Synucleinopathy

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DNA damage and metabolic mechanisms of cancer drug resistance

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Cancer Drug Resistance 2022年第2期5卷 368-379页

作者： Deanna Tiek Shi-Yuan Cheng The ken&ruth davee department of neurology Lou and Jean Malnati Brain Tumor Institute at Northwestern MedicineRobert H.Lurie Comprehensive Cancer Centerand Simpson Querry Institute for EpigeneticsNorthwestern UniversityFeinberg School of Medicine303 E Superior StChicagoIL 60611USA

Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment *** many pivotal advances have been made in first combination therapies,then targeted therapies,and now broadening out to immunomodulatory drugs or metabolic targeting compounds,drug resistance is still ultimately universally *** this brief review,we will discuss different strategies that have been used to fight drug resistance from synthetic lethality to tumor microenvironment modulation,focusing on the DNA damage response and tumor metabolism both within tumor cells and their surrounding *** this way,with a better understanding of both targetable mutations in combination with the metabolism,smarter drugs may be designed to combat cancer drug resistance.

关键词： metabolism damage drugs

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Noncoding RNAs in cancer and cancer stem cells

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Chinese Journal of Cancer 2013年第11期32卷 582-593页

作者： Tianzhi Huang Angel Alvarez Bo Hu Shi-Yuan Cheng the ken & ruth davee department of neurology Northwestern University Feinberg School of MedicineChicagoIL 60611USA Northwestern Brain Tumor Institute Northwestern University Feinberg School of MedicineChicagoIL 60611USA The Robert H.Lurie Comprehensive Cancer Center Northwestern University Feinberg School of MedicineChicagoIL 60611USA Center of Molecular Medicine Northwestern University Feinberg School of MedicineChicagoIL 60611USA

In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long noncoding RNAs(lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.

关键词：非编码RNA 干细胞癌症 miRNA RNA序列生物学功能微RNA 基因表达

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Tumor microenvironment signaling and therapeutics in cancer progression

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Cancer Communications 2023年第5期43卷 525-561页

作者： Anshika Goenka Fatima Khan Bhupender Verma Priyanka Sinha Crismita C.Dmello Manasi PJogalekar Prakash Gangadaran Byeong-Cheol Ahn The ken&ruth davee department of neurology The Robert H.Lurie Comprehensive Cancer CenterNorthwestern University Feinberg School of MedicineChicago60611ILUSA department of Neurological Surgery Feinberg School of MedicineNorthwestern UniversityChicago60611ILUSA department of Ophthalmology Schepens Eye Research InstituteMassachusetts Eye and Ear InfirmaryHarvard Medical SchoolBoston02114MAUSA department of neurology MassGeneral Institute for Neurodegenerative DiseaseMassachusetts General HospitalHarvard Medical SchoolCharlestown02129MAUSA Helen Diller Family Comprehensive Cancer Center University of California San FranciscoSan Francisco94143CAUSA BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents Department of Biomedical ScienceSchool of MedicineKyungpook National UniversityDaegu41944South Korea department of Nuclear Medicine School of MedicineKyungpook National UniversityKyungpook National University HospitalDaegu41944South Korea

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and theirmicroenvironment,which comprises stromal cells and extracellular matrix(ECM)components,among other *** cells can adopt new phenotypes to promote tumor cell *** understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these *** this review,we describe the tumor microenvironment(TME)components and associated *** discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME,the immune checkpoints and immunosuppressive chemokines,and currently used inhibitors targeting these *** include both intrinsic and non-autonomous tumor cell signaling pathways in the TME:protein kinase C(PKC)signaling,Notch,and transforming growth factor(TGF-β)signaling,Endoplasmic Reticulum(ER)stress response,lactate signaling,Metabolic reprogramming,cyclic GMP–AMP synthase(cGAS)–stimulator of interferon genes(STING)and Siglec signaling *** also discuss the recent advances in Programmed Cell Death Protein 1(PD-1),Cytotoxic T-Lymphocyte Associated Protein 4(CTLA4),T-cell immunoglobulin mucin-3(TIM-3)and Lymphocyte Activating Gene 3(LAG3)immune checkpoint inhibitors along with the C-C chemokine receptor 4(CCR4)-C-C class chemokines 22(CCL22)/and 17(CCL17),C-C chemokine receptor type 2(CCR2)-chemokine(C-Cmotif)ligand 2(CCL2),C-C chemokine receptor type 5(CCR5)-chemokine(C-C motif)ligand 3(CCL3)chemokine signaling axis in the *** addition,this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME,which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer *** further discuss the systemic

关键词： 3D-model cancer therapy gut microbiota immune signaling metabolism signaling tumor microenvironment

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