Cocaine perturbs mitovesicle biology in the brain

D’Acunzo, Pasquale; Ungania, Jonathan M.; Kim, Yohan; Barreto, Bryana R.; DeRosa, Steven; Pawlik, Monika; Canals‐Baker, Stefanie; Erdjument‐Bromage, Hediye; Hashim, Audrey; Goulbourne, Chris N.; Neubert, Thomas A.; Saito, Masashi; Sershen, Henry; Levy, Efrat

doi:10.1002/jev2.12301

Cited by 15 publications

(22 citation statements)

References 84 publications

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“…Similarly, SLC9A3R1, a regulator of vesicle-mediated transport, also was down-regulated. These proteins have been previously highlighted in CUD research (65)(66)(67)(68)(69). The observed modulation in membrane Fig.…”

Section: Discussionmentioning

confidence: 64%

“…5F). This finding underscores SLC9A3R1's potential importance in mediating transport processes during the cocaine withdrawal phase (69).…”

Section: Further Analysis Of the Nac Proteome After Prolonged Withdrawalmentioning

confidence: 61%

“…Similarly, SLC9A3R1, a regulator of vesicle-mediated transport, also was down-regulated. These proteins have been previously highlighted in CUD research ( 65 – 69 ). The observed modulation in membrane protein expression after prolonged withdrawal highlights the long-lasting impact of cocaine on the NAc proteome, underscoring the importance of considering these changes in the development of therapeutic strategies for CUD.…”

Section: Discussionmentioning

confidence: 93%

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Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Mews,

Sosnick,

Gurung

et al. 2024

Sci. Signal.

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Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), a region that is integral to the brain’s reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors that are intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook a proteomic analysis that spanned membrane, cytosolic, nuclear, and chromatin compartments of the NAc in a mouse model. The results unveiled immediate and sustained proteomic modifications after cocaine exposure and during prolonged withdrawal. We identified congruent protein regulatory patterns during initial cocaine exposure and reexposure after withdrawal, which contrasted with distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicated adaptive and long-lasting molecular responses prompted by cocaine withdrawal. In addition, we identified potential protein translocation events between soluble-nuclear and chromatin-bound compartments, thus providing insight into intracellular protein dynamics after cocaine exposure. Together, our findings illuminate the intricate proteomic landscape that is altered in the NAc by cocaine use and provide a dataset for future research toward potential therapeutics.

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Section: Discussionmentioning

confidence: 64%

“…5F). This finding underscores SLC9A3R1's potential importance in mediating transport processes during the cocaine withdrawal phase (69).…”

Section: Further Analysis Of the Nac Proteome After Prolonged Withdrawalmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Mews,

Sosnick,

Gurung

et al. 2024

Sci. Signal.

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“…Collected astrocyte cell pellets were processed as follows. Briefly, 8 M urea containing protease inhibitors (Complete Mini, Roche Diagnostics, GmbH Mannheim, Germany) was used to solubilize the cells and processed as previously described (D'Acunzo et al, 2023; Villén & Gygi, 2008), with a few modifications: After solubilization, cysteines were reduced with 5 mM final concentration of Dithiothreitol (Pierce DTT, Thermo Scientific, Rockford, IL, USA) followed by alkylation using 14 mM Iodoacetamide (Sigma‐Aldrich, St. Louis, MO, USA). Finally, digestion was carried out “in‐solution” in the presence of 1.6 M urea, supplemented with protease inhibitors and 5 ng/nL endoproteinase Lys‐C, (Mass Spectrometry Grade, Promega, Madison, WI, USA) which was added to each sample for 2 h, followed by Trypsin (Gold, Mass Spectrometry Grade (Promega, Madison, WI, USA)), at 5 ng/μl, overnight.…”

Section: Methodsmentioning

confidence: 99%

Proteomic profiling of interferon‐responsive reactive astrocytes in rodent and human

Prakash,

Erdjument‐Bromage,

O'Dea

et al. 2023

Glia

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Astrocytes are a heterogeneous population of central nervous system glial cells that respond to pathological insults and injury by undergoing a transformation called “reactivity.” Reactive astrocytes exhibit distinct and context‐dependent cellular, molecular, and functional state changes that can either support or disturb tissue homeostasis. We recently identified a reactive astrocyte sub‐state defined by interferon‐responsive genes like Igtp, Ifit3, Mx1, and others, called interferon‐responsive reactive astrocytes (IRRAs). To further this transcriptomic definition of IRRAs, we wanted to define the proteomic changes that occur in this reactive sub‐state. We induced IRRAs in immunopanned rodent astrocytes and human iPSC‐differentiated astrocytes using TNF, IL1α, C1Q, and IFNβ and characterized their proteomic profile (both cellular and secreted) using unbiased quantitative proteomics. We identified 2335 unique cellular proteins, including IFIT2/3, IFITM3, OASL1/2, MX1/2/3, and STAT1. We also report that rodent and human IRRAs secrete PAI1, a serine protease inhibitor which may influence reactive states and functions of nearby cells. Finally, we evaluated how IRRAs are distinct from neurotoxic reactive astrocytes (NRAs). While NRAs are described by expression of the complement protein C3, it was not upregulated in IRRAs. Instead, we found ~90 proteins unique to IRRAs not identified in NRAs, including OAS1A, IFIT3, and MX1. Interferon signaling in astrocytes is critical for the antiviral immune response and for regulating synaptic plasticity and glutamate transport mechanisms. How IRRAs contribute to these functions is unknown. This study provides the basis for future experiments to define the functional roles of IRRAs in the context of neurodegenerative disorders.

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“…In vitro , mitovesicle secretion is induced by mitochondrial stress 68 . Levy's group has also identified several conditions that promote mitovesicle secretion in vivo , including aging, Down syndrome, and chronic cocaine exposure 68,70–72 . Levy proposed that mitovesicles may play a role in mitochondria quality control and responses to oxidative stress.…”

Section: Evs In the Nervous Systemmentioning

confidence: 99%

Exosomes, microvesicles, and other extracellular vesicles—a Keystone Symposia report

Cable¹,

Witwer

Coffey

et al. 2023

Annals of the New York Academy of Sciences

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Extracellular vesicles (EVs) are small, lipid‐bilayer‐bound particles released by cells that can contain important bioactive molecules, including lipids, RNAs, and proteins. Once released in the extracellular environment, EVs can act as messengers locally as well as to distant tissues to coordinate tissue homeostasis and systemic responses. There is a growing interest in not only understanding the physiology of EVs as signaling particles but also leveraging them as minimally invasive diagnostic and prognostic biomarkers (e.g., they can be found in biofluids) and drug‐delivery vehicles. On October 30–November 2, 2022, researchers in the EV field convened for the Keystone symposium “Exosomes, Microvesicles, and Other Extracellular Vesicles” to discuss developing standardized language and methodology, new data on the basic biology of EVs and potential clinical utility, as well as novel technologies to isolate and characterize EVs.

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Cocaine perturbs mitovesicle biology in the brain

Cited by 15 publications

References 84 publications

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Proteomic profiling of interferon‐responsive reactive astrocytes in rodent and human

Exosomes, microvesicles, and other extracellular vesicles—a Keystone Symposia report

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