Journal: Neurobiology of disease

Article Title: The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus

doi: 10.1016/j.nbd.2025.107084

Figure Lengend Snippet: The Seahorse XF Cell Mito Stress Test was performed using synaptosomes isolated from 8 to 9-month-old male hTau, hTau/PKO, and hTau/Parkin W402A mice. Oxygen consumption rate (OCR) line graphs for (A) hTau/PKO and (C) hTau/Parkin W402A compared to hTau mice. Line graph data presented as mean ± SEM. Calculated respiration profiles for (B) hTau/PKO and (D) hTau/Parkin W402A compared to hTau mice. Significance: p < 0.01**, two-way ANOVA (hTau/PKO vs hTau: interaction DF = 5, respiration profiles DF = 5, genotype DF = 1, and residual DF = 60; hTau/Parkin W402A vs hTau: interaction DF = 5, respiration profiles DF = 5, genotype DF = 1, and residual DF = 48) followed by Šidák ’ s multiple comparisons test. n = 5–6 mice per group. Extracellular acidification rate (ECAR) line graphs for (E) hTau/PKO and (G) hTau/ Parkin W402A compared to hTau mice. Calculated glycolytic profiles for (F) hTau/PKO and (H) hTau/Parkin W402A compared to hTau mice. Significance: p < 0.05*, two-way ANOVA (hTau/PKO vs hTau: interaction DF = 2, respiration profiles DF = 2, genotype DF = 1, and residual DF = 30; hTau/Parkin W402A vs hTau: interaction DF = 2, respiration profiles DF = 2, genotype DF = 1, and residual DF = 30) followed by Šidák’s multiple comparisons test. n = 5–6 mice per group. Violin plot data presented with median and quartiles indicated with dashed lines. DF = degrees of freedom; O = oligomycin, complex V inhibitor; F = FCCP, uncoupler; R/A = rotenone/antimycin A, complex I/III inhibitors.

Article Snippet: Congenic mice used for this study were generated by intercrossing human tau transgenic mice (hTau, JAX strain #005491, overexpress all six non-mutant human tau isoforms in the absence of murine tau) with either parkin knockout mice (PKO, JAX strain #006582) or mutant parkin mice (Parkin W402A , Taconic strain #15143, now available as JAX strain #029317, CRISPR/Cas9 generated mice carrying mutant Parkin W402A ), then backcrossing the progeny to the hTau strain for a minimum of ten generations.

Techniques: Isolation

Journal: Neurobiology of disease

Article Title: The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus

doi: 10.1016/j.nbd.2025.107084

Figure Lengend Snippet: Brain homogenate and synaptic mitochondria were isolated from 8 to 9-month-old WT, hTau, hTau/PKO, and hTau/Parkin W402A mice to assess the levels of select proteins using immunoblotting. Representative immunoblots for parkin in (A) brain and (B) synaptic mitochondria as well as (E) ubiquitin in synaptic mitochondria along with their corresponding loading controls (actin for brain, VDAC1 + 3 for synaptic mitochondria). Quantification of the levels of parkin in (C) brain homogenate (normalized to actin) and in (D) synaptic mitochondria (normalized to VDAC1 + 3) as well as (F) ubiquitin in synaptic mitochondria (normalized to VDAC1 + 3). Significance: p < 0.05*, 0.01**, one-way ANOVA (Brain (parkin): genotype DF = 2, and residual DF = 15; synaptic mitochondria (parkin): genotype DF = 2, and residual DF = 14; synaptic mitochondria (ubiquitin): genotype DF = 3, and residual DF = 19) followed by Tukey’s multiple comparisons test. n = 5–6 mice per group. Violin plot data presented with median and quartiles indicated with dashed lines. DF = degrees of freedom.

Article Snippet: Congenic mice used for this study were generated by intercrossing human tau transgenic mice (hTau, JAX strain #005491, overexpress all six non-mutant human tau isoforms in the absence of murine tau) with either parkin knockout mice (PKO, JAX strain #006582) or mutant parkin mice (Parkin W402A , Taconic strain #15143, now available as JAX strain #029317, CRISPR/Cas9 generated mice carrying mutant Parkin W402A ), then backcrossing the progeny to the hTau strain for a minimum of ten generations.

Techniques: Isolation, Western Blot, Ubiquitin Proteomics

Journal: Neurobiology of disease

Article Title: The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus

doi: 10.1016/j.nbd.2025.107084

Figure Lengend Snippet: Heatmap representing enriched (A) metabolic and (B) signaling pathways produced by IPA canonical pathway analysis comparing all the studied conditions. Score filter p -value cutoff = 1.3 (log10) and z-score cutoff = 1 (absolute value). Blue blocks and orange blocks represent inhibited and activated pathways, respectively. Gray dots represent pathways that did not achieve significance in the given experimental comparison. Heatmaps show the GSEA enrichment scores (NES) and adjusted p -value for the identified Gene Ontology Biological Processes (GO BP) that were significantly changed in (C) hTau vs WT, (D) hTau/PKO vs hTau, and (E) hTau/Parkin W402A vs hTau synaptosomes. n = 5 mice per group. Enrichment analysis was performed in the R software using a p -value cutoff of <0.05. The Benjamini–Hochberg postdoc test was then applied for the generation of adjusted p -values.

Article Snippet: Congenic mice used for this study were generated by intercrossing human tau transgenic mice (hTau, JAX strain #005491, overexpress all six non-mutant human tau isoforms in the absence of murine tau) with either parkin knockout mice (PKO, JAX strain #006582) or mutant parkin mice (Parkin W402A , Taconic strain #15143, now available as JAX strain #029317, CRISPR/Cas9 generated mice carrying mutant Parkin W402A ), then backcrossing the progeny to the hTau strain for a minimum of ten generations.

Techniques: Protein-Protein interactions, Produced, Comparison, Software

Journal: Neurobiology of disease

Article Title: The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus

doi: 10.1016/j.nbd.2025.107084

Figure Lengend Snippet: Volcano plots showing DEPs based on p -value obtained from Ms. Stats (−log 10 ) and log 2 for the 9298 identified proteins. Significance was determined by using p -value cutoff = 1.3 (log 10 ) and z-score cutoff = 1 (absolute value). Blue = significantly downregulated proteins. Red = Significantly upregulated proteins. (A) hTau vs WT synaptosome proteomic comparison showed a total of 333 DEPs, 149 upregulated and 184 downregulated. (B) hTau/PKO vs hTau synaptosome proteomic comparison showed a total of 327 DEPs, 179 upregulated and 148 downregulated. (C) hTau/Parkin W402A vs hTau synaptosome proteomic comparison showed a total of 262 DEPs, 135 upregulated and 127 downregulated. n = 5 mice per group. The five most highly enriched and depleted proteins are annotated in each comparison.

Article Snippet: Congenic mice used for this study were generated by intercrossing human tau transgenic mice (hTau, JAX strain #005491, overexpress all six non-mutant human tau isoforms in the absence of murine tau) with either parkin knockout mice (PKO, JAX strain #006582) or mutant parkin mice (Parkin W402A , Taconic strain #15143, now available as JAX strain #029317, CRISPR/Cas9 generated mice carrying mutant Parkin W402A ), then backcrossing the progeny to the hTau strain for a minimum of ten generations.

Techniques: Comparison

Journal: Neurobiology of disease

Article Title: The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus

doi: 10.1016/j.nbd.2025.107084

Figure Lengend Snippet: The STRING database was used for network analysis of the hTau vs WT, hTau/PKO vs hTau, and hTau/Parkin W402A vs hTau DEPs. The k-means clustering method was used under a high confidence interaction score (min. Interaction score = 0.7). (A) Network representation for the top upregulated and downregulated cluster of proteins in the hTau vs WT comparison. (B) Network representation for the top upregulated and downregulated cluster of proteins in the hTau/PKO vs hTau comparison. (C) Network representation for the top upregulated and downregulated cluster of proteins in the hTau/Parkin W402A vs hTau comparison. n = 5 mice per group. The Gene Ontology Biological Process (GO BP), KEGG, and Reactome databases were used to identify changed pathways.

Article Snippet: Congenic mice used for this study were generated by intercrossing human tau transgenic mice (hTau, JAX strain #005491, overexpress all six non-mutant human tau isoforms in the absence of murine tau) with either parkin knockout mice (PKO, JAX strain #006582) or mutant parkin mice (Parkin W402A , Taconic strain #15143, now available as JAX strain #029317, CRISPR/Cas9 generated mice carrying mutant Parkin W402A ), then backcrossing the progeny to the hTau strain for a minimum of ten generations.

Techniques: Comparison

Journal: Neurobiology of disease

Article Title: The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus

doi: 10.1016/j.nbd.2025.107084

Figure Lengend Snippet: (A) Representative confocal z-stack images of the DG from 8 to 9-month-old male hTau, hTau/PKO, and hTau/Parkin W402A (hTau/W402A) stained with total Tau (green), AT8 (pTauSer202 + pTauT205, red), and DAPI (blue). Objective = 60×, scale bar = 50 μm. (B) Hippocampal quantifications of the % co-localization between total Tau and AT8 in the DG and the whole hippocampus (integration of DG + CA1 + CA3). (C) Representative confocal z-stack images of the parietal cortex from 8 to 9-month-old male hTau, hTau/PKO, and hTau/Parkin W402A stained with total Tau (green), AT8 (pTauSer202 + pTauT205, red), and DAPI (blue). Objective = 60×, scale bar = 50 μm. (D) Quantification of the % co-localization between total Tau and AT8 in the parietal cortex. Significance: p < 0.05*, one-way ANOVA (DG: genotype DF = 2, and residual DF = 18. Hippocampus: genotype DF = 2, and residual DF = 16. Cortex: genotype DF = 2, and residual DF = 19) followed by Tukey’s multiple comparisons test. n = 6–8 mice per group. Violin plot data presented with median and quartiles indicated with dashed lines. DF = degrees of freedom.

Article Snippet: Congenic mice used for this study were generated by intercrossing human tau transgenic mice (hTau, JAX strain #005491, overexpress all six non-mutant human tau isoforms in the absence of murine tau) with either parkin knockout mice (PKO, JAX strain #006582) or mutant parkin mice (Parkin W402A , Taconic strain #15143, now available as JAX strain #029317, CRISPR/Cas9 generated mice carrying mutant Parkin W402A ), then backcrossing the progeny to the hTau strain for a minimum of ten generations.

Techniques: Staining