Dickson, Dennis W

Abstract BRCA1 plays important roles in several biological events during the DNA damage response (DDR). We aimed to determine whether cytoplasmic accumulation of BRCA1 or its phosphorylated form, pBRCA1, is specific to cytoplasmic inclusions in tauopathies, or if it also occurs in α-synuclein-positive inclusions in Lewy body disease (LBD). Using brain tissue from pure LBD, LBD with Alzheimer disease (AD) co-pathology (LBD-AD), and control cases, the immunohistochemical distributions of BRCA1, pBRCA1, its binding partner BARD1, and 53BP1 were examined. The results showed that pBRCA1 (Ser1423) and BARD1 accumulated in brainstem-type Lewy bodies (LBs), whereas only pBRCA1 (Ser1423) was present in cortical-type LBs. There was no significant difference in the frequency of pBRCA1 (Ser1423)-positive LBs between the pure LBD and LBD-AD cases. pBRCA1 (Ser1423) was minimally detected in neuronal nuclei in controls and was absent in neuronal nuclei in LBD cases. In control and LBD cases, 53BP1-immunoreactive deposits were present in the neuronal nuclei. Thus, DDR dysfunction due to cytoplasmic sequestration of pBRCA1 (Ser1423) may play a role in LBD pathogenesis. Additionally, the selective accumulation of BARD1 in brainstem-type LBs, but not cortical-type LBs, points to distinct mechanisms in the formation of these inclusion types, offering further insights into LBD pathology.

Abstract Mass spectrometry (MS) is a technique widely employed for the identification and characterization of proteins, with personalized medicine, systems biology, and biomedical applications. The application of MS-based proteomics advances our understanding of protein function, cellular signaling, and complex biological systems. MS data analysis is a critical process that includes identifying and quantifying proteins and peptides and then exploring their biological functions in downstream analyses. To address the complexities associated with MS data analysis, we developed ProtPipe to streamline and automate the processing and analysis of high-throughput proteomics and peptidomics datasets with DIA-NN preinstalled. The pipeline facilitates data quality control, sample filtering, and normalization, ensuring robust and reliable downstream analyses. ProtPipe provides downstream analyses, including protein and peptide differential abundance identification, pathway enrichment analysis, protein–protein interaction analysis, and major histocompatibility complex (MHC)–peptide binding affinity analysis. ProtPipe generates annotated tables and visualizations by performing statistical post-processing and calculating fold changes between predefined pairwise conditions in an experimental design. It is an open-source, well-documented tool available at https://github.com/NIH-CARD/ProtPipe, with a user-friendly web interface.

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)–derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration–approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

Abstract Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A knockout (CgA-KO) mice. This study investigates the role of CgA in Alzheimer’s disease (AD) and corticobasal degeneration (CBD). CgA ablation in tauopathy mice (hTau) (CgA-KO/hTau) exhibited reduced tau aggregation, spreading, extended lifespan, and improved cognitive function. Transcriptomic and metabolite analysis of mouse cortices revealed altered alpha1-adrenergic receptors (Adra1) and high epinephrine (EPI) levels in hTau mice compared to WT mice, mirroring observations in AD and CBD patients. CgA-KO/hTau mice exhibited a reversal of EPI levels in the cortex and the expression of Adra1, nearly returning them to WT levels. Treatment of hippocampal slices with EPI or Adra1 agonist intensified, while an Adra1 antagonist inhibited tau hyperphosphorylation and aggregation. These findings highlight the interplay between the EPI-Adra signaling system and CgA in tauopathy.