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Cited by 1Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingMitochondrial Function and Pathology

Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism

Open access
Ayala, Daniela A., Hall, Grace M., Das, Debanjana, Tijerina, Eliana, Villagran, Luisa Lopez, Khan, Zaid, Paliwal, Devanshi, Anand, Anu +2 more·2026·Cellular and Molecular Neurobiology
DOI 10.1007/s10571-026-01713-xPMC PMC12424766
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Abstract

Parkinson's disease (PD) is the fastest growing neurological disorder with no known cure. Our ability to develop disease-modifying treatments that slow down the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is hindered by a dearth of knowledge on roles for non-neuronal elements such as astrocytes during PD pathogenesis. More specifically, the extent to which mitochondrial DNA (mtDNA) damage in SNc astrocytes contributes to SNc DA neuron loss during PD remains unknown. To address this knowledge gap, we utilized an adeno-associated virus (AAV) called Mito-PstI that expresses the restriction enzyme PstI as an approach to damage mtDNA in SNc astrocytes and assess the effect of astrocytic mtDNA damage on SNc DA neuron function and viability in mice. Mito-PstI-induced mtDNA damage in SNc astrocytes disrupted mitochondrial morphology, caused increased wrapping of SNc astrocytic processes around SNc DA neurons, and abnormally increased dopamine release by SNc DA neuron axonal terminals within the dorsolateral striatum (DLS). In addition, mice injected with Mito-PstI in the SNc showed increased spontaneous and apomorphine-induced rotations contralateral to the side with SNc Mito-PstI injections. In further experiments, we used a parkinsonian mouse model with low dose 6-hydroxydopamine (6-OHDA) injection into the DLS to show that Mito-PstI expression in SNc astrocytes caused a worsening of 6-OHDA-induced spontaneous contralateral rotational behavior, and exacerbated SNc DA neuron loss. These results suggest that mitochondria in SNc astrocytes are not only critical for the function of SNc DA neurons, but are also a new target for developing disease-modifying strategies against PD. Main Points: Mito-PstI expression in mouse SNc astrocytes increases dopamine releaseMito-PstI expression in SNc astrocytes worsens contralateral rotational behavior in miceMito-PstI expression in SNc astrocytes increases DA neuron loss in 6-OHDA mice.

AI snapshot

Written from the paper’s full text.

TL;DR

Using an AAV-based Mito-PstI tool to damage mitochondrial DNA in substantia nigra pars compacta (SNc) astrocytes, this study found increased S100B+ astrocytic process density, abnormally increased ACh-evoked dopamine release in the dorsolateral striatum, and increased contralateral rotations in mice. In a low-dose 6-OHDA parkinsonian model, astrocytic mtDNA damage worsened spontaneous rotational behavior and exacerbated SNc dopaminergic neuron loss.

Key findings

  • Mito-PstI expression in SNc astrocytes did not change mitochondrial particle number, area, or size (p = 0.186, p = 0.180, p = 0.638), but significantly increased S100B+ astrocytic process density (34.14 ± 2.50 vs. 42.24 ± 2.34; p = 0.039) without changing GFAP area or intensity.
  • ACh-evoked dopamine release in the dorsolateral striatum was ~40% greater in Mito-PstI mice (GRABDA AUC: 1761.46 ± 213.92 vs. 2942.43 ± 403.08 A.U. × sec; p = 0.015).
  • Mito-PstI alone increased spontaneous and apomorphine-induced contralateral rotations (three-way ANOVA p = 0.0016 and p = 0.009, respectively) but was not sufficient to cause SNc dopaminergic neuron loss.
  • In mice given low-dose 6-OHDA into the dorsolateral striatum, Mito-PstI worsened spontaneous contralateral rotations (p < 0.0001) and exacerbated SNc dopaminergic neuron loss, with ~50% greater decrease in TH+ neuron number ratio (0.882 ± 0.088 vs. 0.408 ± 0.078; p < 0.0001) and ~60% decreases in TH area and intensity.

Methods

  • Two- to three-month-old C57BL/6 male and female mice received unilateral stereotaxic SNc injections of Mito-GFP control or Mito-GFP + Mito-PstI AAVs; some also received dorsolateral striatum injections of AAV-GRABDA and/or low-dose 6-OHDA (3 µg).
  • Three protocols assessed: live DLS brain-slice imaging of ACh-evoked GRABDA dopamine release; longitudinal spontaneous and apomorphine-induced contralateral rotations; and 6-OHDA parkinsonism with TH, S100B, and GFAP immunostaining plus mitochondrial morphology quantification.
  • Analyses used two-sample t-tests or Mann-Whitney tests for two-group comparisons and three-way ANOVA for rotational behavior; male and female mice were combined because no sex differences were observed.

Limitations

  • The paper does not state a dedicated limitations section; no stated limitations are present in the provided text.
  • Evident from the text: findings are restricted to mice using AAV-expressed PstI to damage astrocytic mtDNA and a low-dose 6-OHDA model, so direct relevance to human PD or other PD models is not established.
  • Evident from the text: Mito-PstI alone did not cause SNc dopaminergic neuron loss, and exacerbation required 6-OHDA, suggesting astrocytic mtDNA damage may act as a secondary insult; some readouts also used small samples (e.g., mitochondrial morphology n = 4 control, n = 6 experimental; GFAP n = 5 control, n = 7 experimental).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s10571-026-01713-x

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

5 tests recomputed · 0 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

36 of 46 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Unilateral damage to the SNc can cause contralateral rotations in mice via postsynaptic and/or presynaptic mechanisms.

    “unilateral damage to the SNc can cause contralateral rotations in mice via postsynaptic and/or presynaptic mechanisms.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Zarate et al. 2025 source

      The Results report increased rotations after unilateral striatal 6-OHDA lesions, and the Discussion links the rotations to SNc dopamine-neuron loss and describes both striatal receptor sensitivity and dopamine release as influences. However, the measured rotations were induced by apomorphine, and the lesion was made in the striatum, not directly in the SNc; the claim omits those conditions. The supplied passages and indexed results give section labels but no page numbers. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Konieczny et al. 2016 source
  • Premisecitation

    Overexpression of TH in mice results in hyperoxidative stress, which can eventually lead to accelerated SNc DA neuron loss.

    “overexpression of TH in mice, which is the rate limiting enzyme for dopamine synthesis results in hyperoxidative stress, which can eventually lead to accelerated SNc DA neuron loss (Vecchio et al. 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Vecchio et al. 2021 source

      The Results and Discussion report that TH-overexpressing mice developed markers of oxidative stress, including elevated striatal H2O2 and reduced glutathione. The Discussion raises dopaminergic cell degeneration as a possible pathway for future study, but does not show that these mice undergo accelerated SNc dopamine-neuron loss. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • Rests on an assumption: TH is the rate-limiting enzyme for dopamine synthesis.
  • Premisecitation

    Spontaneous and apomorphine-induced rotational assays detect imbalances in dopamine release and/or changes in dopamine receptor sensitivity in the striatum, leading to contralateral rotational behavior.

    “Spontaneous and apomorphine-induced rotational assays detect imbalances in dopamine release and/or changes in dopamine receptor sensitivity in the striatum, leading to abnormal rotational behavior in mice in a direction that is contralateral to the side with either excessive striatal dopamine release and/or abnormally increased postsynaptic D1 and D2 dopamine receptor activation (Zarate et al. 202”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Zarate et al. 2025 source

      The Discussion (page unavailable) links apomorphine-induced contralateral rotations to activation of hypersensitive striatal dopamine receptors and describes a possible contribution from dopamine release and D1 activation on the lesioned side. The Methods (page unavailable) describe an apomorphine-induced assay, but the copy does not establish the claim about spontaneous rotations or specifically implicate D2 activation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Patients with clinical PD possess an increased accumulation of mtDNA mutations in blood cells.

    “recent studies have shown that patients with clinical PD possess an increased accumulation of mtDNA mutations in blood cells (Qi et al. 2023; Tresse et al. 2023)”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Qi et al. 2023

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Tresse et al. 2023 source

      The Discussion reports an increased presence of mtDNA mutations in patients with PD, and the Results describe mtDNA alterations in PD brain samples. Neither passage establishes that the mutations accumulate in blood cells; searches for blood cells and peripheral blood did not find that finding in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Astrocytes within the substantia nigra pars compacta outnumber neurons.

    “astrocytes within the SNc are an important non-neuronal target to consider during PD pathogenesis because these cells not only outnumber neurons”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Gonzalez-Perez et al. 2015 source

      The paper states that astrocytes outnumber neurons across the brain (Abstract; no page given). It does not report a count or ratio for the substantia nigra pars compacta, so the region-specific claim is not established by this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 24
  • The quote only partly states this claim. 6

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The brain alone consumes 20% of the total energy required by the body, and central nervous system mitochondria meet a majority of this massive energy requirement for the brain.

    “The brain alone consumes 20% of the total energy required by the body, and central nervous system (CNS) mitochondria meet a majority of this massive energy requirement for the brain”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Cunnane et al. 2020 source
    • cites Panov et al. 2014 source

      Section 4 says brain functions depend on aerobic mitochondrial energy metabolism, supporting the claim that mitochondria meet much of the brain’s energy needs. But the paper does not say the brain consumes 20% of the body’s energy. Its 20% figure, in Section 5, refers instead to the share of the adult brain’s energy supplied by fatty-acid oxidation; page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The release of dopamine by SNc DA neurons can act on somatodendritic D2 receptors, thereby inhibiting dopamine release at DA axonal terminals in the striatum.

    “previous studies have shown that the release of dopamine by SNc DA neurons can act on somatodendritic D2 receptors, thereby inhibiting dopamine release at DA axonal terminals in the striatum (Cragg and Greenfield 1997; Hikima et al. 2021; Sulzer et al. 2016).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Cragg and Greenfield 1997 source

      The ‘D2 receptor modulation of somatodendritic DA release in SNc’ section reports that D2 receptors autoinhibit dopamine release in the SNc. The ‘D2 receptor control of axon terminal DA release’ section separately reports D2 inhibition of release at striatal terminals. Neither passage shows that dopamine acting on somatodendritic D2 receptors inhibits release at those terminals; the paper compares the two sites rather than establishing that causal link. Page numbers are not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Hikima et al. 2021 source
    • cites Sulzer et al. 2016 source

      Section 1.4 says D2 receptors occur on the somatodendritic portions of midbrain dopamine neurons and that D2 autoreceptors inhibit striatal dopamine release. It also distinguishes regulation at midbrain cell bodies from local regulation at striatal axons and focuses on the latter. The passages do not establish the claimed sequence in which dopamine released by SNc neurons activates somatodendritic D2 receptors and thereby inhibits release at striatal terminals. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Mutations in Parkinson's disease-related risk genes present in astrocytes have been shown to cause mitochondrial dysfunction, which can potentially be detrimental to surrounding neurons.

    “Mutations in PD-related risk genes that are present in astrocytes have been shown to cause mitochondrial dysfunction, which can potentially be detrimental to surrounding neurons”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Booth et al. 2017 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Astrocytic mitochondria are highly active organelles, displaying a wide panorama of Ca2+ influx events that robustly respond to neurotransmitter agonists.

    “Astrocytic mitochondria are highly active organelles, displaying a wide panorama of Ca2+ influx events that robustly respond to neurotransmitter agonists”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Huntington and Srinivasan 2021 source

  • May combine two claims.

    Premisecitation

    The AAV Mito-PstI expresses PstI under control of the astrocyte-specific GfaABC1D promoter, is directed to the astrocytic mitochondrial matrix by a mito7 targeting signal, and cuts mitochondrial DNA at PstI recognition sites, thereby damaging mtDNA only in astrocytes within pre-specified Mito-PstI injected brain regions in vivo.

    “Our novel AAV called Mito-PstI, expresses the restriction enzyme PstI under control of the astrocyte-specific GfaABC1D promoter.”
    • Also stated in: § Effect of Mito-PstI on the Morphology of Mitochondria in SNc Astrocytes · plain
      “AAV-expressed PstI is directed to the astrocytic mitochondrial matrix by a mitochondria-specific mito7 targeting signal sequence (Mito), where this restriction enzyme cuts mtDNA at PstI recognition sites in mice, thereby damaging mtDNA only in astrocytes within pre-specified Mito-PstI injected brain regions in vivo”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ayala et al. 2024 source

  • May combine two claims.

    Interpretationcitation

    Sustained increases in dopamine release within the striatum could result in the toxic accumulation of hyperoxidative dopamine metabolites such as reactive oxygen species and dopamine quinones, causing a dying back of SNc DA axons in the striatum and thereby leading to the accelerated loss of SNc DA neurons.

    “Together, these reports suggest that sustained increases in dopamine release within the striatum could result in the toxic accumulation of hyperoxidative dopamine metabolites such as reactive oxygen species and dopamine quinones, causing a dying back of SNc DA axons in the striatum and thereby leading to the accelerated loss of SNc DA neurons.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Lam et al. 2011 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Vecchio et al. 2021 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    GRABDA is an optogenetic sensor for dopamine.

    “The DLS of mice was first injected with an AAV expressing GRABDA, which is an optogenetic sensor for dopamine (Sun et al. 2018).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Sun et al. 2018 source

      The Abstract identifies GRABDA as a genetically encoded fluorescent sensor for dopamine. The Discussion distinguishes the sensor from optogenetic stimulation, which was used to elicit dopamine release; it does not describe GRABDA itself as an optogenetic sensor. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The morphology of astrocytic mitochondria in the SNc is distinct from the fusiform morphology previously reported in DLS astrocytes and resembles astrocytic mitochondria in the dentate gyrus of the hippocampus.

    “This distinct morphology is in stark contrast to the fusiform morphology of mitochondria previously reported by us in DLS astrocytes and resembles astrocytic mitochondria in the dentate gyrus of the hippocampus (Ayala et al. 2024; Huntington and Srinivasan 2021).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Ayala et al. 2024 source

      The Results section reports that astrocytic mitochondria in the dentate gyrus are smaller and less abundant than those in the DLS, supporting a regional morphological contrast. The paper does not describe DLS mitochondria as fusiform or compare either region’s mitochondria with those in the SNc. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Huntington and Srinivasan 2021 source

      The sections on DLS mitochondrial size and on DLS–hippocampus differences report morphological variation in DLS astrocytes and compare DLS with hippocampal CA1 astrocytes (pages not supplied). They do not describe DLS mitochondria as fusiform or examine dentate gyrus or SNc mitochondria, so they cannot establish the specific resemblance and contrast claimed. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    The specific role of substantia nigra pars compacta astrocytic mitochondria in contributing to neurodegeneration is a relatively unexplored but active area of investigation.

    “the specific role of SNc astrocytic mitochondria in contributing to neurodegeneration is a relatively unexplored, but active area of investigation”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Bantle et al. 2020 source

      The “Astrocyte Mitochondrial Function and Dysfunction in PD” section (page unavailable) calls astrocytic mitochondrial dysfunction an emerging field and suggests it may contribute to PD progression. However, “Astrocytes and Therapeutic Considerations in PD” (page unavailable) focuses on mitochondria in striatal astrocytes supporting SNpc axons; it does not establish the specific role of mitochondria in astrocytes located in the SNpc. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Gollihue and Norris 2020 source

      The Abstract and Discussion describe astrocytic mitochondria as an increasingly studied contributor to neuronal protection and damage in neurodegenerative disease. They do not establish that this research concerns astrocytic mitochondria specifically in the substantia nigra pars compacta; the Discussion’s substantia nigra example concerns mitochondrial transplantation and neuronal sparing instead. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    After unilateral loss of SNc DA neurons, apomorphine activates hypersensitive postsynaptic D1 and D2 dopamine receptors in MSNs within the DLS on the SNc damaged side, resulting in apomorphine-induced contralateral rotations.

    “A known postsynaptic mechanism is that after unilateral loss of SNc DA neurons, apomorphine activates hypersensitive postsynaptic D1 and D2 dopamine postsynaptic receptors in MSNs within the DLS on the SNc damaged side, which results in apomorphine-induced contralateral rotations (Zarate et al. 2025).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Zarate et al. 2025 source

      The Discussion (page unavailable) says apomorphine-induced rotations arise from activation of hypersensitive dopamine receptors in striatal medium spiny neurons after a unilateral lesion, and it specifically discusses D1 receptors and contralateral rotations. The Methods identify the lesion site as the DLS. Our copy does not identify D2 receptors as part of this mechanism, so that specificity is unsupported. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Changes in astrocyte coverage within neural structures can affect the concentration of extrasynaptic neurotransmitters, thereby modulating the function of nearby neurons.

    “multiple studies have shown that changes in astrocyte coverage within neural structures can affect the concentration of extrasynaptic neurotransmitters, thereby modulating the function of nearby neurons (Lawal et al. 2022).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Lawal et al. 2022 source

  • May combine two claims.

    Premisecitation

    Compromised function in astrocytic mitochondria could have profound detrimental effects on neuronal function within the substantia nigra pars compacta, corroborated by evidence that SNc astrocytes demonstrate deficiencies in mitochondrial oxidative phosphorylation protein complex expression in postmortem samples of patients with clinically diagnosed Parkinson's disease.

    “Compromised function in astrocytic mitochondria could have profound detrimental effects on neuronal function within the SNc”
    • Also stated in: § Introduction · boosted
      “SNc astrocytes demonstrate deficiencies in mitochondrial oxidative phosphorylation (OXPHOS) protein complex expression in postmortem samples of patients with clinically diagnosed PD”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Chen et al. 2022 source

  • May combine two claims.

    Premisecitation

    Non-cell autonomous mechanisms can cause dysfunction across the entire substantia nigra pars compacta, leading to rapid dopaminergic neurodegeneration, in contrast to neuron-specific cell autonomous mechanisms.

    “in contrast to neuron-specific cell autonomous mechanisms that affect individual DA neurons within the SNc, non-cell autonomous mechanisms can cause dysfunction across the entire SNc, thereby leading to rapid DA neurodegeneration”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Dawson 2008 source
    • cites di Domenico et al. 2019 source

      The Abstract and Discussion report that PD-derived astrocytes contribute to dopaminergic-neuron degeneration, including in co-culture with control neurons. The Introduction identifies the substantia nigra pars compacta as a site of dopaminergic-neuron loss, but the paper does not show dysfunction across the entire region, establish rapid degeneration, or make the stated comparison with neuron-specific mechanisms. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Gleichman and Carmichael 2020 source

      Section 3.5 (Parkinson’s disease; page not provided) discusses glial involvement in neurodegeneration and suggests that microglial reactivity may drive PD pathogenesis. It does not say that non-cell-autonomous mechanisms cause dysfunction across the entire substantia nigra pars compacta or rapid dopaminergic neurodegeneration, nor does it make the stated comparison with neuron-specific mechanisms. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Chronic global mtDNA damage in all central nervous system cells in mice causes profound morphological changes in astrocytes.

    “a previous report has shown that chronic global mtDNA damage in all central nervous system cells in mice causes profound morphological changes in astrocytes (Ignatenko et al. 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Ignatenko et al. 2018 source

      The Results section, “Loss of mtDNA maintenance activates astrocytes” (page unavailable), reports progressive activation and reactive morphology in astrocytes after mtDNA depletion. But the paper depleted mtDNA in astrocytes or neurons in separate mouse models, not globally in all central nervous system cells; that condition in the citing sentence is unsupported. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mitochondria in central nervous system astrocytes are strategically distributed within subcellular regions in the astrocytic territory, endfeet and soma, and since astrocytes generally outnumber neurons in the CNS, astrocytic mitochondria are optimally positioned to cater to the high energy demands of CNS neurons, particularly substantia nigra pars compacta dopaminergic neurons.

    “Mitochondria in CNS astrocytes are strategically distributed within subcellular regions in the astrocytic territory, endfeet and soma”
    • Also stated in: § Introduction · plain
      “astrocytic mitochondria are optimally positioned to cater to the high energy demands of CNS neurons, and particularly, SNc DA neurons”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Ayala et al. 2024 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Huntington and Srinivasan 2021 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Zarate et al. 2023 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • The quote only partly states this claim.

    Findingown data

    Apomorphine caused a significant increase in contralateral rotations on days 21, 28, 35, and 42 in Mito-PstI mice compared to Mito-GFP controls (F(1, 68) = 7.19, p = 0.009).

    “However, the D1/D2 receptor agonist, apomorphine caused a significant increase in contralateral rotations on days 21, 28, 35 and 42 after AAV injections in the Mito-GFP + Mito-PstI injected mice when compared to control Mito-GFP injected mice (Fig. 4C)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mito-PstI expression in SNc astrocytes induces mitochondrial DNA damage.
    • Rests on an assumption: AAVs injected into the SNc express Mito-GFP or Mito-GFP + Mito-PstI specifically in astrocytes.
    • Rests on an assumption: Mito-GFP expression alone (control) does not affect the measured outcomes.

  • The quote only partly states this claim.

    Findingown data

    Two weeks after AAV injection, Mito-PstI mice showed a significant increase in spontaneous contralateral rotations compared to Mito-GFP controls (11 ± 1.39 vs 42.07 ± 11.78, p = 0.044).

    “Two weeks after unilateral Mito-GFP or Mito-GFP + Mito-PstI injection into the SNc, we found a significant increase in spontaneous contralateral rotations in experimental Mito-GFP + Mito-PstI mice when compared control Mito-GFP mice (Fig. 6C)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mito-PstI expression in SNc astrocytes induces mitochondrial DNA damage.
    • Rests on an assumption: AAVs injected into the SNc express Mito-GFP or Mito-GFP + Mito-PstI specifically in astrocytes.
    • Rests on an assumption: Mito-GFP expression alone (control) does not affect the measured outcomes.

  • The quote only partly states this claim.

    Findingown data

    No differences in AAV-injected/uninjected SNc ratios for cell number between Mito-PstI and Mito-GFP mice (0.724 ± 0.081 vs 0.786 ± 0.100, p = 0.649).

    “There were no differences in AAV-Injected/Uninjected SNc ratios between control Mito-GFP and experimental Mito-GFP + Mito-PstI mice for either cell number (Fig. 5D)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mito-PstI expression in SNc astrocytes induces mitochondrial DNA damage.
    • Rests on an assumption: AAVs injected into the SNc express Mito-GFP or Mito-GFP + Mito-PstI specifically in astrocytes.
    • Rests on an assumption: Mito-GFP expression alone (control) does not affect the measured outcomes.

  • The quote only partly states this claim.

    Findingown data

    No significant difference in TH labeled neuron area between Mito-PstI and Mito-GFP mice (p = 0.496 and p = 0.83).

    “There was also no significant difference in TH labeled neuron area between Mito-GFP and Mito-GFP + PstI mice (Fig. 5E)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mito-PstI expression in SNc astrocytes induces mitochondrial DNA damage.
    • Rests on an assumption: AAVs injected into the SNc express Mito-GFP or Mito-GFP + Mito-PstI specifically in astrocytes.
    • Rests on an assumption: Mito-GFP expression alone (control) does not affect the measured outcomes.

  • The quote only partly states this claim.

    Findingown data

    Mito-PstI expression in SNc astrocytes significantly increased spontaneous contralateral rotations on days 21, 28, 35, and 42 compared to Mito-GFP controls (F(1, 68) = 10.81, p = 0.0016).

    “On days 21, 28, 35 and 42, contralateral spontaneous rotations in experimental mice co-expressing Mito-GFP + Mito-PstI in the SNc were significantly increased when compared to control mice expressing Mito-GFP in the SNc (Fig. 4B)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mito-PstI expression in SNc astrocytes induces mitochondrial DNA damage.
    • Rests on an assumption: AAVs injected into the SNc express Mito-GFP or Mito-GFP + Mito-PstI specifically in astrocytes.
    • Rests on an assumption: Mito-GFP expression alone (control) does not affect the measured outcomes.

  • May combine two claims.

    Findingown data

    In mice with low dose 6-OHDA-induced parkinsonism, Mito-PstI expression in the SNc causes a persistent increase in spontaneous contralateral rotations across multiple weeks and results in an ~50% greater loss of DA neurons in the SNc.

    “in mice with low dose 6-OHDA-induced parkinsonism, Mito-PstI expression in the SNc not only causes a persistent increase in spontaneous contralateral rotations across multiple weeks (Fig. 6C) but also results in an ~ 50% greater loss of DA neurons in the SNc (Fig. 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mito-PstI-induced astrocytic mtDNA damage in the SNc is accompanied by an increase in astrocytic process density with no change in GFAP intensity or area.

    “Mito-PstI-induced astrocytic mtDNA damage in the SNc is accompanied by an increase in astrocytic process density (Fig. 2A and C) with no change in GFAP intensity or area (Fig. 2E, F and G).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Following low dose 6-OHDA into the DLS, spontaneous rotations were significantly increased on days 28, 35, and 42 in Mito-PstI + 6-OHDA mice compared to Mito-GFP + 6-OHDA controls (F(1, 81) = 15.65, p < 0.0001).

    “Following injection of low dose 6-OHDA into the DLS, spontaneous rotations were significantly increased on days 28, 35 and 42 in experimental 6-OHDA + Mito-GFP + Mito-PstI injected mice when compared to control 6-OHDA + Mito-GFP injected mice (Fig. 6C)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mito-PstI expression in SNc astrocytes induces mitochondrial DNA damage.
    • Rests on an assumption: AAVs injected into the SNc express Mito-GFP or Mito-GFP + Mito-PstI specifically in astrocytes.
    • Rests on an assumption: Mito-GFP expression alone (control) does not affect the measured outcomes.

  • May combine two claims.

    Interpretationown data

    Mito-PstI expression in mouse SNc astrocytes causes SNc DA neurons to become dysfunctional, evidenced by increased ACh-evoked dopamine release and increased rotations.

    “Although we did not observe a loss of SNc DA neurons with Mito-PstI expression in SNc astrocytes, our data show that Mito-PstI expression in mouse SNc astrocytes causes SNc DA neurons to become dysfunctional, which is evidenced by abnormal increases in ACh-evoked dopamine release within the DLS (Fig. 3), as well as an increase in spontaneous and apomorphine-induced contralateral rotations in Mito”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mito-PstI expression in SNc astrocytes induces mitochondrial DNA damage.
    • Rests on an assumption: AAVs injected into the SNc express Mito-GFP or Mito-GFP + Mito-PstI specifically in astrocytes.
    • Rests on an assumption: Mito-GFP expression alone (control) does not affect the measured outcomes.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All detection settings on Ethovision were maintained constant across cohorts of mice.

    “All detection settings on Ethovision were maintained constant across cohorts of mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The increase in contralateral rotations in Mito-PstI mice is likely due to abnormal in vivo presynaptic increases in dopamine release within the DLS, rather than postsynaptic hypersensitive D1/D2 receptors.

    “Furthermore, our data in Fig. 4D that directly compare spontaneous versus apomorphine-induced contralateral rotations in Mito-PstI expressing mice suggest that rather than a postsynaptic induction of hypersensitive D1/D2 dopamine receptors in DLS medium spiny neurons (MSNs) due to Mito-PstI expression in SNc astrocytes, it is likely that abnormal in vivo presynaptic increases in dopamine release”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mito-PstI expression in SNc astrocytes induces mitochondrial DNA damage.
    • Rests on an assumption: AAVs injected into the SNc express Mito-GFP or Mito-GFP + Mito-PstI specifically in astrocytes.
    • Rests on an assumption: Mito-GFP expression alone (control) does not affect the measured outcomes.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    An accumulation of mtDNA mutations in CNS astrocytes could contribute to the progression of clinical PD.

    “which invokes the intriguing view that an accumulation of mtDNA mutations in CNS astrocytes could contribute to the progression of clinical PD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Three independent quantitative readouts (TH+ neuron number, TH area, TH intensity) were used to assess SNc DA neuron loss.

    “We employed three independent quantitative readouts of SNc DA neuron loss in TH labeled midbrain sections: (i) The number of TH + SNc DA neurons, (ii) TH labeled area in the SNc, and (iii) The intensity of SNc TH fluorescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Mito-PstI expression in the SNc likely causes an abnormal increase in presynaptic dopamine release by SNc axonal terminals in the DLS in vivo, which significantly increases contralateral rotations in mice expressing Mito-PstI in SNc astrocytes.

    “suggests that Mito-PstI expression in the SNc likely causes an abnormal increase in presynaptic dopamine release by SNc axonal terminals in the DLS in vivo, which significantly increases contralateral rotations in mice expressing Mito-PstI in SNc astrocytes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Study design and conductnone given

    Beveled glass injection pipettes possess a small pore diameter of approximately 6 μm, which minimizes damage to the brain as well as injury-related astrocyte reactivity at the injection site.

    “Beveled glass injection pipettes possess a small pore diameter of ~ 6 μm, which minimizes damage to the brain as well as injury-related astrocyte reactivity at the injection site.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Confocal parameters such as excitation intensity, HV, gain and offset were maintained constant for each condition.

    “Confocal parameters such as excitation intensity, HV, gain and offset were maintained constant for each condition.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Astrocytic mitochondria in central nervous system astrocytes can be morphologically heterogeneous, perhaps depending on energy demands of the brain region in which they reside.

    “These data further demonstrate that astrocytic mitochondria in central nervous system astrocytes can be morphologically heterogenous, perhaps depending on energy demands of the brain region in which they reside.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    mtDNA damage specifically in SNc astrocytes causes an abnormal increase in dopamine release within the striatum, leading to an exacerbation of SNc DA neuron loss.

    “For the first time, this study shows that mtDNA damage, specifically in SNc astrocytes causes an abnormal increase in dopamine release within the striatum, leading to an exacerbation of SNc DA neuron loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    mtDNA damage in SNc astrocytes worsens parkinsonian behavioral deficits and SNc DA neuron loss by abnormally increasing presynaptic dopamine release at SNc DA neuron axonal terminals within the DLS.

    “we infer that mtDNA damage in SNc astrocytes worsens parkinsonian behavioral deficits and SNc DA neuron loss by abnormally increasing presynaptic dopamine release at SNc DA neuron axonal terminals within the DLS.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Increased density of Mito-PstI expressing astrocytic processes in the SNc could reduce extracellular dopamine levels in the SNc via enhanced astrocytic reuptake of released dopamine in the SNc, thereby altering ACh-evoked dopamine release in DA axonal terminals within the DLS.

    “Therefore, we surmise that increased density of Mito-PstI expressing astrocytic processes in the SNc could reduce extracellular dopamine levels in the SNc via enhanced astrocytic reuptake of released dopamine in the SNc, thereby altering ACh-evoked dopamine release in DA axonal terminals within the DLS.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The increase in density of astrocytic processes around the soma of SNc DA neurons by Mito-PstI-expressing astrocytes alters autoregulatory pathways governing dopamine release in the DLS.

    “One mechanistic explanation for this result is that the increase in density of astrocytic processes around the soma of SNc DA neurons by Mito-PstI-expressing astrocytes (Fig. 2C) alters autoregulatory pathways governing dopamine release in the DLS.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Confocal parameters such as LED power, voltage, gain, offset and aperture diameter remained constant during live imaging sessions.

    “During all live imaging sessions, confocal parameters such as LED power, voltage, gain, offset and aperture diameter remained constant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    mtDNA damage in SNc astrocytes could cause SNc DA neuron dysfunction, thereby worsening neurodegeneration during PD.

    “our study demonstrates that mtDNA damage in SNc astrocytes could indeed cause SNc DA neuron dysfunction, thereby worsening neurodegeneration during PD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    An increase in contralateral rotations could be caused by either abnormal presynaptic axonal dopamine release by SNc DA neurons or hypersensitive postsynaptic D1/D2 dopamine receptors.

    “An increase in contralateral rotations could be caused by either abnormal presynaptic axonal dopamine release by SNc DA neurons (Konieczny et al. 2016) and/or hypersensitive postsynaptic D1/D2 dopamine receptors (Creese et al. 1977; Groppetti et al. 1986; Rouillard et al. 1987).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Konieczny et al. 2016 source
    • cites Creese et al. 1977 source
    • cites Groppetti et al. 1986

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A presynaptic mechanism could depend on excessive dopamine release by axonal terminals of SNc neurons in the DLS on the side with SNc damage, which can result in increased contralateral rotational behavior.

    “a presynaptic mechanism could depend on excessive dopamine release by axonal terminals of SNc neurons in the DLS on the side with SNc damage, which can also similarly result in increased contralateral rotational behavior (Konieczny et al. 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Konieczny et al. 2016 source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Expression of Mito-PstI in the SNc disrupts D2 receptor-mediated SNc somatodendritic DA neuron autoregulation of axonal dopamine due to reduced levels of extracellular dopamine in the SNc.

    “Based on this rationale, we suggest the possibility that expression of Mito-PstI in the SNc disrupts D2 receptor-mediated SNc somatodendritic DA neuron autoregulation of axonal dopamine due to reduced levels of extracellular dopamine in the SNc.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Apomorphine activates 6-OHDA-induced hypersensitive postsynaptic D1 and D2 receptors in DLS MSN neurons, which could override the rotational behavior caused by increased dopamine release within the DLS of 6-OHDA treated Mito-PstI mice.

    “This result suggests that the D1/D2 receptor agonist, apomorphine activates 6-OHDA-induced hypersensitive postsynaptic D1 and D2 receptors in DLS MSN neurons, which could override the rotational behavior caused by increased dopamine release within the DLS of 6-OHDA treated Mito-PstI mice.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Apomorphine is a D1/D2 receptor agonist.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The 420 s window with bath applied acetylcholine for measuring mean GRABDA fluorescence area under the curve values was maintained constant across all live brain slice fields of view and mice.

    “For consistency, the 420 s window with bath applied ACh for measuring mean GRABDA fluorescence AUC values was maintained constant across all live brain slice FOVs and mice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All experiments were performed in accordance with Texas A&M University Institutional Animal Care and Use Committee approved guidelines.

    “All experiments were performed in accordance with Texas A&M University Institutional Animal Care and Use Committee approved guidelines (IACUC #2022 − 0252).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Injected/uninjected SNc ratios were used to control for differences in antibody staining and confocal imaging artifacts.

    “This approach enabled us to extract injected/uninjected SNc ratios for each of the three readouts as an additional method to control for differences in antibody staining as well as confocal imaging-related artifacts across multiple midbrain sections.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Astrocytic mtDNA damage results in a compromised state of SNc astrocytes under baseline conditions, which could predispose to an acceleration of SNc DA neuron loss following a PD-related secondary insult.

    “We interpret our finding as astrocytic mtDNA damage resulting in a compromised state of SNc astrocytes under baseline conditions, which could predispose to an acceleration of SNc DA neuron loss following a PD-related secondary insult.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    No sex differences were observed, so male and female mice were combined for all experimental readouts in this study.

    “Because we did not observe any sex differences, we combined male and female mice for all experimental readouts in this study.”
    Quote in the paperNot a substantial claim
47 of 47

  • The paper relies on this without support.

    Mito-PstI expression in SNc astrocytes induces mitochondrial DNA damage.

    “Mito-PstI-induced mtDNA damage”

  • The paper relies on this without support.

    AAVs injected into the SNc express Mito-GFP or Mito-GFP + Mito-PstI specifically in astrocytes.

    “Mito-PstI expression in SNc astrocytes”

  • The paper relies on this without support.

    Mito-GFP expression alone (control) does not affect the measured outcomes.

    “Mito-GFP (control mice)”

  • The paper relies on this without support.

    TH is the rate-limiting enzyme for dopamine synthesis.

    “which is a rate limiting enzyme for dopamine synthesis”

  • The paper relies on this without support.

    Apomorphine is a D1/D2 receptor agonist.

    “the D1/D2 receptor agonist, apomorphine”
5 of 5

Statistics that don’t add up

Each reported p-value recomputed from its test statistic and degrees of freedom.

  • p-value fits an unstated one-tailed test: F(1, 81) = 15.65, p < .0001

    Minor

    The paper reports p < .0001 here; recomputing from the test statistic and its degrees of freedom gives p < .001. The reported value is what a one-tailed test gives, but the paper does not say near this result that a one-tailed test was used.

    Reported p < .0001 · recomputed p < .001

1 of 1

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Doesn’t add upF(1, 81) = 15.65reported p < .0001 · recomputed p < .001

    “F(1, 81) = 15.65, p < .0001”

  • ConsistentF(1, 68) = 10.81reported p = .0016 · recomputed p = .002

    “F(1, 68) = 10.81, p = .0016”

  • ConsistentF(1, 68) = 7.19reported p = .009 · recomputed p = .009

    “F(1, 68) = 7.19, p = .009”

  • ConsistentF(1, 56) = 8.32reported p = .006 · recomputed p = .006

    “F(1, 56) = 8.32, p = .006”

  • ConsistentF(1, 78) = 2.73reported p = .103 · recomputed p = .102

    “F(1, 78) = 2.73, p = .103”

5 of 5

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The stated universal injection rate conflicts with the 6-OHDA rate

    Major

    The 6-OHDA injection is specified at 0.25 μl/min, but the same surgery section says all injections were performed at 0.3 μL/min.

  • Two different 6-OHDA injection volumes are specified

    Minor

    The surgery methods specify a 0.6 μl injection, whereas the results describe the same 3 μg DLS dose as delivered in 1 μl.

  • Day-21 spontaneous rotations are described as increased despite a lower mean

    Minor

    The experimental group's day-21 mean is 14.67 rotations, below the control group's 15.67, contradicting the statement that it increased on that day.

3 of 3

Cites

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Cited by

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Related

Authors
Ayala, D. A., Hall, G. M., Das, D., Tijerina, E., Villagran, L. L., Khan, Z., Paliwal, D., Anand, A., Rimer, M., & Srinivasan, R.
Affiliations
Texas A&M University (US)
Corresponding author
Srinivasan, Rahul
ORCID
Venue
Cellular and Molecular Neurobiology
Publisher
Springer Science and Business Media LLC
Published
2026-03-19
Volume
46
Issue
1
ISSN
  • 0272-4340 (ISSN-L)
  • 1573-6830
DOI
10.1007/s10571-026-01713-x
PMC
PMC12424766
OpenAlex
W7138830231
Semantic Scholar
000b4b9d64ea93e9aad68ae4df37eb4e68218598
Cited by
1
References
47
Citations by year
2026: 1
FWCI
4.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Neurobiology (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institute of General Medical Sciences (T32GM135748)
  • National Institute of Neurological Disorders and Stroke (R21NS121959)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Parkinson's disease, mitochondrial DNA damage, substantia nigra pars compacta, astrocytes, dopaminergic neuron loss, 6-hydroxydopamine, S100B, dopamine release, dorsolateral striatum, contralateral rotation, disease-modifying therapy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-02.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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