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Article ; Online: Corrigendum for "Mass Spectrometry-Based Proteomics Analysis of Human Substantia Nigra From Parkinson's Disease Patients Identifies Multiple Pathways Potentially Involved in the Disease".

Jang, Yura / Pletnikova, Olga / Troncoso, Juan C / Pantelyat, Alexander Y / Dawson, Ted M / Rosenthal, Liana S / Na, Chan Hyun

Molecular & cellular proteomics : MCP

2023 Volume 22, Issue 6, Page(s) 100570

Language	English
Publishing date	2023-06-02
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2023.100570
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Article ; Online: Small RNA Profiles of Brain Tissue-Derived Extracellular Vesicles in Alzheimer's Disease.

Huang, Yiyao / Driedonks, Tom A P / Cheng, Lesley / Turchinovich, Andrey / Pletniková, Olga / Redding-Ochoa, Javier / Troncoso, Juan C / Hill, Andrew F / Mahairaki, Vasiliki / Zheng, Lei / Witwer, Kenneth W

Journal of Alzheimer's disease : JAD

2023

Abstract: Background: Extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) are emerging contributors to Alzheimer's disease (AD) pathophysiology. Differential abundance of ncRNAs carried by EVs may provide valuable insights into underlying disease mechanisms. ...

Abstract	Background: Extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) are emerging contributors to Alzheimer's disease (AD) pathophysiology. Differential abundance of ncRNAs carried by EVs may provide valuable insights into underlying disease mechanisms. Brain tissue-derived EVs (bdEVs) are particularly relevant, as they may offer valuable insights about the tissue of origin. However, there is limited research on diverse ncRNA species in bdEVs in AD. Objective: This study explored whether the non-coding RNA composition of EVs isolated from post-mortem brain tissue is related to AD pathogenesis. Methods: bdEVs from age-matched late-stage AD patients (n = 23) and controls (n = 10) that had been separated and characterized in our previous study were used for RNA extraction, small RNA sequencing, and qPCR verification. Results: Significant differences of non-coding RNAs between AD and controls were found, especially for miRNAs and tRNAs. AD pathology-related miRNA and tRNA differences of bdEVs partially matched expression differences in source brain tissues. AD pathology had a more prominent association than biological sex with bdEV miRNA and tRNA components in late-stage AD brains. Conclusions: Our study provides further evidence that EV non-coding RNAs from human brain tissue, including but not limited to miRNAs, may be altered and contribute to AD pathogenesis.
Language	English
Publishing date	2023-09-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-230872
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Article ; Online: Ubiquitin-positive astrogliopathy clinically mimicking Parkinson's disease.

Morris, Meaghan / Moghekar, Abhay / Guo, Haidan / Pletnikova, Olga / Redding-Ochoa, Javier / Albert, Marilyn / Resnick, Susan M / Chen, Liam

Acta neuropathologica communications

2022 Volume 10, Issue 1, Page(s) 164

Abstract: Several neurodegenerative pathologies can clinically mimic Parkinson's disease, including neurodegenerative diseases with glial pathology. However, the glial aggregates are typically composed of known pathogenic proteins and are associated with prominent ...

Abstract	Several neurodegenerative pathologies can clinically mimic Parkinson's disease, including neurodegenerative diseases with glial pathology. However, the glial aggregates are typically composed of known pathogenic proteins and are associated with prominent neuronal loss in the substantia nigra. Here we present an unusual case of a 91-year-old man with a clinical diagnosis of Parkinson's disease, but whose autopsy findings showed a ubiquitin-positive astrogliopathy without significant neuronal loss in the substantia nigra. These glial aggregates affected the basal ganglia, cortex, and cerebellum, and were negative for tau, alpha-synuclein, TDP-43, FUS, and p62. This case is a rare example of an unknown glial neurodegenerative pathology mimicking Parkinson's disease without significant loss of nigral dopaminergic neurons.
MeSH term(s)	Humans ; Male ; Aged, 80 and over ; Parkinson Disease/pathology ; Ubiquitin/metabolism ; alpha-Synuclein/metabolism ; Substantia Nigra/metabolism ; Neurodegenerative Diseases/pathology ; Neuroglia/pathology
Chemical Substances	Ubiquitin ; alpha-Synuclein
Language	English
Publishing date	2022-11-14
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-022-01464-y
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Article ; Online: Loss of Astrocytic µ Opioid Receptors Exacerbates Aversion Associated with Morphine Withdrawal in Mice: Role of Mitochondrial Respiration.

Murlanova, Kateryna / Jouroukhin, Yan / Novototskaya-Vlasova, Ksenia / Huseynov, Shovgi / Pletnikova, Olga / Morales, Michael J / Guan, Yun / Kamiya, Atsushi / Bergles, Dwight E / Dietz, David M / Pletnikov, Mikhail V

Cells

2023 Volume 12, Issue 10

Abstract: Astrocytes express mu/µ opioid receptors, but the function of these receptors remains poorly understood. We evaluated the effects of astrocyte-restricted knockout of µ opioid receptors on reward- and aversion-associated behaviors in mice chronically ... ...

Abstract	Astrocytes express mu/µ opioid receptors, but the function of these receptors remains poorly understood. We evaluated the effects of astrocyte-restricted knockout of µ opioid receptors on reward- and aversion-associated behaviors in mice chronically exposed to morphine. Specifically, one of the floxed alleles of the
MeSH term(s)	Mice ; Animals ; Morphine/adverse effects ; Astrocytes ; Receptors, Opioid ; Narcotic Antagonists/pharmacology ; Naloxone/pharmacology ; Mice, Knockout ; Receptors, Opioid, mu/genetics
Chemical Substances	Morphine (76I7G6D29C) ; Receptors, Opioid ; Narcotic Antagonists ; Naloxone (36B82AMQ7N) ; Receptors, Opioid, mu
Language	English
Publishing date	2023-05-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12101412
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Article ; Online: Mass Spectrometry-Based Proteomics Analysis of Human Substantia Nigra From Parkinson's Disease Patients Identifies Multiple Pathways Potentially Involved in the Disease.

Jang, Yura / Pletnikova, Olga / Troncoso, Juan C / Pantelyat, Alexander Y / Dawson, Ted M / Rosenthal, Liana S / Na, Chan Hyun

Molecular & cellular proteomics : MCP

2022 Volume 22, Issue 1, Page(s) 100452

Abstract: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) of the brain. Despite decades of studies, the precise pathogenic mechanism of PD is still ... ...

Abstract	Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) of the brain. Despite decades of studies, the precise pathogenic mechanism of PD is still elusive. An unbiased proteomic analysis of PD patient's brain allows the identification of critical proteins and molecular pathways that lead to dopamine cell death and α-synuclein deposition and the resulting devastating clinical symptoms. In this study, we conducted an in-depth proteome analysis of human SN tissues from 15 PD patients and 15 healthy control individuals combining Orbitrap mass spectrometry with the isobaric tandem mass tag-based multiplexing technology. We identified 10,040 proteins with 1140 differentially expressed proteins in the SN of PD patients. Pathway analysis showed that the ribosome pathway was the most enriched one, followed by gamma-aminobutyric acidergic synapse, retrograde endocannabinoid signaling, cell adhesion molecules, morphine addiction, Prion disease, and PD pathways. Strikingly, the majority of the proteins enriched in the ribosome pathway were mitochondrial ribosomal proteins (mitoribosomes). The subsequent protein-protein interaction analysis and the weighted gene coexpression network analysis confirmed that the mitoribosome is the most enriched protein cluster. Furthermore, the mitoribosome was also identified in our analysis of a replication set of ten PD and nine healthy control SN tissues. This study provides potential disease pathways involved in PD and paves the way to study further the pathogenic mechanism of PD.
MeSH term(s)	Humans ; Parkinson Disease/metabolism ; Proteomics/methods ; Substantia Nigra/metabolism ; Brain/metabolism ; Neurodegenerative Diseases/metabolism
Language	English
Publishing date	2022-11-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2022.100452
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Article ; Online: Deficient mitochondrial respiration in astrocytes impairs trace fear conditioning and increases naloxone-precipitated aversion in morphine-dependent mice.

Murlanova, Kateryna / Jouroukhin, Yan / Huseynov, Shovgi / Pletnikova, Olga / Morales, Michael J / Guan, Yun / Baraban, Jay M / Bergles, Dwight E / Pletnikov, Mikhail V

Glia

2022 Volume 70, Issue 7, Page(s) 1289–1300

Abstract: Mitochondria are abundant in the fine processes of astrocytes, however, potential roles for astrocyte mitochondria remain poorly understood. In the present study, we performed a systematic examination of the effects of abnormal oxidative phosphorylation ... ...

Abstract	Mitochondria are abundant in the fine processes of astrocytes, however, potential roles for astrocyte mitochondria remain poorly understood. In the present study, we performed a systematic examination of the effects of abnormal oxidative phosphorylation in astrocytes on several mouse behaviors. Impaired astrocyte oxidative phosphorylation was produced by astrocyte-specific deletion of the nuclear mitochondrial gene, Cox10, that encodes an accessory protein of complex IV, the protoheme:heme-O-farnesyl transferase. As expected, conditional deletion of the Cox10 gene in mice (cKO mice) significantly reduced expression of COX10 and Cytochrome c oxidase subunit I (MTCO1) of Complex IV, resulting in decreased oxidative phosphorylation without significantly affecting glycolysis. No effects of the deletion were observed on locomotor activity, anxiety-like behavior, nociception, or spontaneous alternation. Cox10 cKO female mice exhibited mildly impaired novel object recognition, while Cox10 cKO male mice were moderately deficient in trace fear conditioning. No group-related changes were observed in conditional place preference (CPP) that assessed effects of morphine on reward. In contrast to CPP, Cox10 cKO mice demonstrated significantly increased aversive behaviors produced by naloxone-precipitated withdrawal following chronic exposure to morphine, that is, jumping and avoidance behavior as assessed by conditional place aversion (CPA). Our study suggests that astrocyte oxidative phosphorylation may contribute to behaviors associated with greater cognitive load and/or aversive and stressful conditions.
MeSH term(s)	Alkyl and Aryl Transferases/metabolism ; Animals ; Astrocytes/metabolism ; Fear ; Female ; Male ; Membrane Proteins/metabolism ; Mice ; Mitochondria/metabolism ; Morphine/metabolism ; Morphine/pharmacology ; Morphine Dependence/metabolism ; Morphine Dependence/psychology ; Naloxone/metabolism ; Naloxone/pharmacology ; Narcotic Antagonists/metabolism ; Narcotic Antagonists/pharmacology ; Respiration ; Substance Withdrawal Syndrome/metabolism ; Substance Withdrawal Syndrome/psychology
Chemical Substances	Membrane Proteins ; Narcotic Antagonists ; Naloxone (36B82AMQ7N) ; Morphine (76I7G6D29C) ; Alkyl and Aryl Transferases (EC 2.5.-) ; COX10 protein, mouse (EC 2.5.1.-)
Language	English
Publishing date	2022-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.24169
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Article: Towards a human brain EV atlas: Characteristics of EVs from different brain regions, including small RNA and protein profiles.

Huang, Yiyao / Arab, Tanina / Russell, Ashley E / Mallick, Emily R / Nagaraj, Rajini / Gizzie, Evan / Redding-Ochoa, Javier / Troncoso, Juan C / Pletnikova, Olga / Turchinovich, Andrey / Routenberg, David A / Witwer, Kenneth W

bioRxiv : the preprint server for biology

2023

Abstract: Extracellular vesicles (EVs) are released from different cell types in the central nervous system (CNS) and play roles in regulating physiological and pathological functions. Although brain-derived EVs (bdEVs) have been successfully collected from brain ... ...

Abstract	Extracellular vesicles (EVs) are released from different cell types in the central nervous system (CNS) and play roles in regulating physiological and pathological functions. Although brain-derived EVs (bdEVs) have been successfully collected from brain tissue, there is not yet a "bdEV atlas" of EVs from different brain regions. To address this gap, we separated EVs from eight anatomical brain regions of a single individual and subsequently characterized them by count, size, morphology, and protein and RNA content. The greatest particle yield was from cerebellum, while the fewest particles were recovered from the orbitofrontal, postcentral gyrus, and thalamus regions. EV surface phenotyping indicated that CD81 and CD9 were more abundant than CD63 for all regions. Cell-enriched surface markers varied between brain regions. For example, putative neuronal markers NCAM, CD271, and NRCAM were more abundant in medulla, cerebellum, and occipital regions, respectively. These findings, while restricted to tissues from a single individual, suggest that additional studies are merited to lend more insight into the links between EV heterogeneity and function in the CNS.
Language	English
Publishing date	2023-05-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.06.539665
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Article ; Online: Toward a human brain extracellular vesicle atlas: Characteristics of extracellular vesicles from different brain regions, including small RNA and protein profiles.

Interdisciplinary medicine

2023 Volume 1, Issue 4, Page(s) e20230016

Abstract	Extracellular vesicles (EVs) are released from different cell types in the central nervous system (CNS) and play roles in regulating physiological and pathological functions. Although brain-derived EVs (bdEVs) have been successfully collected from brain tissue, there is not yet a "bdEV Atlas" of EVs from different brain regions. To address this gap, we separated EVs from eight anatomical brain regions of a single individual and subsequently characterized them by count, size, morphology, and protein and RNA content. The greatest particle yield was from cerebellum, while the fewest particles were recovered from the orbitofrontal, postcentral gyrus, and thalamus regions. EV surface phenotyping indicated that CD81 and CD9 were more abundant than CD63 in all regions. Cell-enriched surface markers varied between brain regions. For example, putative neuronal markers NCAM, CD271, and NRCAM were more abundant in medulla, cerebellum, and occipital regions, respectively. These findings, while restricted to tissues from a single individual, suggest that additional studies are warranted to provide more insight into the links between EV heterogeneity and function in the CNS.
Language	English
Publishing date	2023-08-15
Publishing country	Germany
Document type	Journal Article
ISSN	2832-6245
ISSN (online)	2832-6245
DOI	10.1002/INMD.20230016
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Article: Transcriptional Signatures of Hippocampal Tau Pathology in Primary Age-Related Tauopathy and Alzheimer's Disease.

Stein-O'Brien, Genevieve L / Palaganas, Ryan / Meyer, Ernest M / Redding-Ochoa, Javier / Pletnikova, Olga / Guo, Haidan / Bell, William R / Troncoso, Juan C / Huganir, Richard L / Morris, Meaghan

medRxiv : the preprint server for health sciences

2023

Abstract: Background: Tau pathology is common in age-related neurodegenerative diseases. Tau pathology in primary age-related tauopathy (PART) and in Alzheimer's disease (AD) has a similar biochemical structure and anatomic distribution, which is distinct from ... ...

Abstract	Background: Tau pathology is common in age-related neurodegenerative diseases. Tau pathology in primary age-related tauopathy (PART) and in Alzheimer's disease (AD) has a similar biochemical structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, the molecular changes associated with intraneuronal tau pathology in PART and AD, and whether these changes are similar in the two diseases, is largely unexplored. Methods: Using GeoMx spatial transcriptomics, mRNA was quantified in CA1 pyramidal neurons with tau pathology and adjacent neurons without tau pathology in 6 cases of PART and 6 cases of AD, and compared to 4 control cases without pathology. Transcriptional changes were analyzed for differential gene expression and for coordinated patterns of gene expression associated with both disease state and intraneuronal tau pathology. Results: Synaptic gene changes and two novel gene expression signatures associated with intraneuronal tau were identified in PART and AD. Overall, gene expression changes associated with intraneuronal tau pathology were similar in PART and AD. Synaptic gene expression was decreased overall in neurons in AD and PART compared to control cases. However, this decrease was largely driven by neurons lacking tau pathology. Synaptic gene expression was increased in tau-positive neurons compared to tau-negative neurons in disease. Two novel gene expression signatures associated with intraneuronal tau were identified by examining coordinated patterns of gene expression. Genes in the up-regulated expression pattern were enriched in calcium regulation and synaptic function pathways, specifically in synaptic exocytosis. These synaptic gene changes and intraneuronal tau expression signatures were confirmed in a published transcriptional dataset of cortical neurons with tau pathology in AD. Conclusions: PART and AD show similar transcriptional changes associated with intraneuronal tau pathology in CA1 pyramidal neurons, raising the possibility of a mechanistic relationship between the tau pathology in the two diseases. Intraneuronal tau pathology was also associated with increased expression of genes associated with synaptic function and calcium regulation compared to tau-negative disease neurons. The findings highlight the power of molecular analysis stratified by pathology in neurodegenerative disease and provide novel insight into common molecular pathways associated with intraneuronal tau in PART and AD.
Language	English
Publishing date	2023-09-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.12.23295440
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Article ; Online: Brain Tissue-Derived Extracellular Vesicles in Alzheimer's Disease Display Altered Key Protein Levels Including Cell Type-Specific Markers.

Huang, Yiyao / Driedonks, Tom A P / Cheng, Lesley / Rajapaksha, Harinda / Routenberg, David A / Nagaraj, Rajini / Redding, Javier / Arab, Tanina / Powell, Bonita H / Pletniková, Olga / Troncoso, Juan C / Zheng, Lei / Hill, Andrew F / Mahairaki, Vasiliki / Witwer, Kenneth W

Journal of Alzheimer's disease : JAD

2022 Volume 90, Issue 3, Page(s) 1057–1072

Abstract: Background: Brain tissue-derived extracellular vesicles (bdEVs) play neurodegenerative and protective roles, including in Alzheimer's disease (AD). Extracellular vesicles (EVs) may also leave the brain to betray the state of the CNS in the periphery. ... ...

Abstract	Background: Brain tissue-derived extracellular vesicles (bdEVs) play neurodegenerative and protective roles, including in Alzheimer's disease (AD). Extracellular vesicles (EVs) may also leave the brain to betray the state of the CNS in the periphery. Only a few studies have profiled the proteome of bdEVs and source brain tissue. Additionally, studies focusing on bdEV cell type-specific surface markers are rare. Objective: We aimed to reveal the pathological mechanisms inside the brain by profiling the tissue and bdEV proteomes in AD patients. In addition, to indicate targets for capturing and molecular profiling of bdEVs in the periphery, CNS cell-specific markers were profiled on the intact bdEV surface. Methods: bdEVs were separated and followed by EV counting and sizing. Brain tissue and bdEVs from age-matched AD patients and controls were then proteomically profiled. Total tau (t-tau), phosphorylated tau (p-tau), and antioxidant peroxiredoxins (PRDX) 1 and 6 were measured by immunoassay in an independent bdEV separation. Neuron, microglia, astrocyte, and endothelia markers were detected on intact EVs by multiplexed ELISA. Results: Overall, concentration of recovered bdEVs was not affected by AD. Proteome differences between AD and control were more pronounced for bdEVs than for brain tissue. Levels of t-tau, p-tau, PRDX1, and PRDX6 were significantly elevated in AD bdEVs compared with controls. Release of certain cell-specific bdEV markers was increased in AD. Conclusion: Several bdEV proteins are involved in AD mechanisms and may be used for disease monitoring. The identified CNS cell markers may be useful tools for peripheral bdEV capture.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Proteome/metabolism ; Brain/pathology ; Extracellular Vesicles/metabolism ; Neurons/metabolism
Chemical Substances	Proteome
Language	English
Publishing date	2022-10-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-220322
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