{
  "abstract": "Aberrant signaling by leucine-rich repeat kinase 2 (LRRK2) drives Parkinson’s disease (PD) biology, linking Rab phosphorylation to endolysosomal dysfunction. However, how LRRK2-linked trafficking intersects with metabolic remodeling within vulnerable human substantia nigra cell states remains poorly defined. Here, phosphatome-wide systems analysis, single-nucleus transcriptomics, structural modeling, and independent phosphoproteomic evidence were integrated to identify the glycolytic regulator PFKFB2 as a phosphorylation-associated metabolic node. Sample-level pseudobulk profiling of a human substantia nigra single-nucleus RNA-seq data set revealed distributed phosphatome remodeling across the PD spectrum, prioritizing PFKFB2 as a transcriptionally reduced, dynamically rewired systems hub. Full-atlas analysis across 390,360 nuclei showed that this tissue-level decrease resolved into disease-stage-specific cellular redistribution: PFKFB2 was reduced across oligodendrocyte-lineage and neuronal compartments in PD, whereas Parkinson’s disease dementia (PDD) showed microglial induction alongside astrocytic and neuronal loss. Stratification by PFKFB2 expression revealed marked transcriptional polarity: PFKFB2-positive cellular states were enriched for LRRK2–Rab trafficking and lysosomal programs, whereas PFKFB2-negative states retained mitochondrial/OXPHOS signatures; paired donor-pseudobulk analysis confirmed that the principal PFKFB2-associated PDD microglial program was reproducible across donors. Structurally, AlphaFold-guided peptide docking identified the flexible C-terminal regulatory tail of PFKFB2 as a kinase-accessible region, prioritizing the conserved Ser483 locus as the strongest LRRK2-compatible structural candidate. Independent phosphoproteomic interrogation of human and mouse LRRK2 perturbation data sets supported the orthologous PFKFB2/Pfkfb2 Ser483/Ser486 region as an LRRK2-responsive phosphosite candidate, exhibiting inhibitor-sensitive reduction and inhibitor-resistant retention under A2016T LRRK2 conditions. Together, these findings position the PFKFB2 signaling axis as a cell-state-resolved metabolic interface linking LRRK2–Rab trafficking with the mitochondrial–endolysosomal disease architecture of the Parkinsonian substantia nigra.",
  "abstract_shown": true,
  "affiliations": [
    "Southern Technical University , , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Adil R. Sarhan",
      "orcid": "0000-0003-2163-4910"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/58bcz1mwqvccv.bib",
  "cited_by": 0,
  "doi": "10.1021/acsomega.6c07768",
  "fulltext_url": "https://europepmc.org/articles/PMC13688533",
  "id": "58bcz1mwqvccv",
  "issns": [
    "2470-1343"
  ],
  "landing_url": "https://pubs.acs.org/acsodf/article/11/41/63655/5445715/Single-Nucleus-Phosphatome-Rewiring-and",
  "language": "eng",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2728|Parkinson's Disease Mechanisms and Treatments"
    ]
  ],
  "openalex": "W7220866396",
  "pdf_url": "https://pubs.acs.org/doi/pdf/10.1021/acsomega.6c07768",
  "pmcid": "PMC13688533",
  "pmid": "42924009",
  "published": "2026-10-07",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/58bcz1mwqvccv.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:39Z",
      "native_id": "10.1021/acsomega.6c07768",
      "source": "crossref",
      "url": "https://pubs.acs.org/acsodf/article/11/41/63655/5445715/Single-Nucleus-Phosphatome-Rewiring-and"
    },
    {
      "first_seen": "2026-10-30T12:20:36Z",
      "native_id": "MED:42924009",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42924009"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Parkinson's Disease Mechanisms and Treatments",
      "subfield": "neurology"
    }
  ],
  "title": "Single-Nucleus Phosphatome Rewiring and Phosphoproteomics Reveal PFKFB2 as an LRRK2-Linked Metabolic Node in Human Parkinsonian Substantia Nigra",
  "title_text": "Single-Nucleus Phosphatome Rewiring and Phosphoproteomics Reveal PFKFB2 as an LRRK2-Linked Metabolic Node in Human Parkinsonian Substantia Nigra",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:36Z",
  "url": "https://research.draconitic.com/paper/58bcz1mwqvccv",
  "venue": "ACS Omega",
  "versions": []
}