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Brain Cell Type-Specific Nuclear Proteomics Is Imperative to Resolve Neurodegenerative Disease Mechanisms.

ABSTRACT: Neurodegenerative diseases (NDs) involve complex cellular mechanisms that are incompletely understood. Emerging findings have revealed that disruption of nuclear processes play key roles in ND pathogenesis. The nucleus is a nexus for gene regulation and cellular processes that together, may underlie pathomechanisms of NDs. Furthermore, many genetic risk factors for NDs encode proteins that are either present in the nucleus or are involved in nuclear processes (for example, RNA binding proteins, epigenetic regulators, or nuclear-cytoplasmic transport proteins). While recent advances in nuclear transcriptomics have been significant, studies of the nuclear proteome in brain have been relatively limited. We propose that a comprehensive analysis of nuclear proteomic alterations of various brain cell types in NDs may provide novel biological and therapeutic insights. This may be feasible because emerging technical advances allow isolation and investigation of intact nuclei from post-mortem frozen human brain tissue with cell type-specific and single-cell resolution. Accordingly, nuclei of various brain cell types harbor unique protein markers which can be used to isolate cell-type specific nuclei followed by down-stream proteomics by mass spectrometry. Here we review the literature providing a rationale for investigating proteomic changes occurring in nuclei in NDs and then highlight the potential for brain cell type-specific nuclear proteomics to enhance our understanding of distinct cellular mechanisms that drive ND pathogenesis.

SUBMITTER: Nelson RS

PROVIDER: S-EPMC9243337 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Herpes simplex virus replicates in the nucleus, where new capsids are assembled. It produces procapsids devoid of nucleic acid but containing the preVP22a scaffold protein. These thermo-unstable particles then mature into A-, B- or C-nuclear icosahedral capsids, depending on their ability to shed the proteolytically processed scaffold and incorporation of the viral genome. To study how these viral capsids differ, we performed proteomics studies of highly enriched HSV-1 A-, B- and C-nuclear capsids, relying in part on a novel and powerful flow virometry approach to purify C-capsids. We found that the viral particles contained the expected capsid components and identified several tegument proteins in the C-capsid fraction (pUL21, pUL36, pUL46, pUL48, pUL49, pUL50, pUL51 and pUS10). Moreover, numerous ribosomal, hnRNPs and other host proteins, absent from the uninfected controls, were detected on the capsids with some of them seemingly specific to C-capsids (glycogen synthase, four different keratin-related proteins, fibronectin 1 and PCBP1). A subsequent proteomics analysis was performed to rule out the presence of protein complexes that may share similar density as the viral capsids but do not otherwise interact with them. Using pUL25 or VP5 mutant viruses incapable of assembling C-nuclear or all nuclear capsids, respectively, we confirmed the bulk of our initial findings. Naturally, it will next be important to address the functional relevance of these proteins.IMPORTANCE Much is known about the biology of herpesviruses. This includes their unique ability to traverse the two nuclear envelopes by sequential budding and fusion steps. For HSV-1, this implies the pUL31/pUL34 and pUL17/pUL25 complexes that may favor C-capsid egress. However, this selection process is not clear, nor are all the differences that distinguish A-, B- and C-capsids. The present study probes what proteins compose these capsids, including host proteins. This should open up new research avenues to clarify the biology of this most interesting family of viruses. It also reiterates the use of flow virometry as an innovative tool to purify viral particles.

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Brain Cell Type-Specific Nuclear Proteomics Is Imperative to Resolve Neurodegenerative Disease Mechanisms.

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