The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index; none of the 19 sources its claims cite is checked for support yet.
Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons
Open accessAbstract
Mitochondrial dysfunction is implicated in the pathophysiology of Parkinson′s disease (PD), a common age-associated neurodegenerative disease characterized by intraneuronal inclusions (Lewy bodies) and progressive degeneration of the nigrostriatal dopamine (DA) system. It has recently been demonstrated that midbrain DA neurons of PD patients and elderly humans contain high levels of somatic mtDNA mutations, which may impair respiratory chain function. However, clinical studies have not established whether the respiratory chain deficiency is a primary abnormality leading to inclusion formation and DA neuron death, or whether generalized metabolic abnormalities within the degenerating DA neurons cause secondary damage to mitochondria. We have used a reverse genetic approach to investigate this question and created conditional knockout mice (termed MitoPark mice), with disruption of the gene for mitochondrial transcription factor A ( Tfam ) in DA neurons. The knockout mice have reduced mtDNA expression and respiratory chain deficiency in midbrain DA neurons, which, in turn, leads to a parkinsonism phenotype with adult onset of slowly progressive impairment of motor function accompanied by formation of intraneuronal inclusions and dopamine nerve cell death. Confocal and electron microscopy show that the inclusions contain both mitochondrial protein and membrane components. These experiments demonstrate that respiratory chain dysfunction in DA neurons may be of pathophysiological importance in PD.
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Written from the paper’s full text.
TL;DR
MitoPark mice with conditional Tfam disruption in midbrain dopamine neurons develop respiratory chain deficiency, adult-onset progressive parkinsonism, intraneuronal inclusions, and dopamine neuron death. The findings provide genetic evidence that respiratory chain dysfunction in dopamine neurons may be pathophysiologically important in Parkinson’s disease.
Key findings
- MitoPark mice had reduced mtDNA expression in midbrain DA neurons at 6 weeks and marked reduction of COX enzyme activity at 20 weeks.
- Motor impairment began at ≈14–15 weeks, progressed to tremor, twitching, and apparent limb rigidity at ≈20 weeks, and mice were killed at ≈45 weeks; L-DOPA improved motor performance, with older mice showing abrupt termination resembling “wearing off.”
- DA innervation loss first appeared in dorsolateral striatum at 12 weeks; TH+ midbrain neuron loss was earlier and more marked in SN than VTA, and 20-week-old MitoPark mice had DA loss plus increased HVA/DA and DOPAC/DA ratios.
- Most midbrain DA neurons contained small cytoplasmic inclusions at 6 weeks before DA cell loss; inclusions contained mitochondrial protein and membrane components by confocal and electron microscopy, but did not contain α-synuclein and persisted in α-synuclein knockout MitoPark mice.
Methods
- Reverse genetic conditional knockout: DAT-cre mice were crossed with TfamloxP/TfamloxP mice to disrupt Tfam in midbrain DA neurons; cre expression was validated by in situ hybridization and reporter mice.
- Behavioral testing used automated activity cages for locomotion and rearing, with L-DOPA plus benserazide or PBS injections; histology, immunohistochemistry, in situ hybridization, electron microscopy, confocal microscopy, and HPLC catecholamine measurements were used.
- Sample sizes included 7 MitoPark/control pairs for in situ hybridization and enzyme histochemistry, 20 pairs for immunohistochemistry, 18 mice (9 littermate pairs) for TH cell counts, and 9 animals for aggregate counts and size measurements.
Limitations
- The paper states that the mechanism whereby respiratory chain deficiency leads to inclusion formation needs to be elucidated, that there was no evidence of α-synuclein in the inclusions, and that there is no absolute link between respiratory chain dysfunction and oxidative stress.
- The text makes evident that this is a mouse model rather than human PD, that the inclusions differ from human Lewy bodies in α-synuclein content, and that the h116–131 antibody reacted with an unknown inclusion component.
- The paper does not include a formal limitations section; additional limitations evident from the text include reliance on a single conditional knockout model and unresolved specificity of one α-synuclein antibody.
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In the paper
“In situ hybridizations detected much reduced expression of the mtDNA-encoded COX subunit I mRNA in DA neurons of substantia nigra (SN) and the ventral tegmental area (VTA) in MitoPark mice at the age of 6 weeks (Fig. 1E).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“accompanied by formation of intraneuronal inclusions and dopamine nerve cell death.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We also found a marked reduction of COX enzyme activity by histochemical analyses of midbrain DA neurons of 20-week-old MitoPark mice (Fig. 1D).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was no increased embryonic or neonatal lethality in MitoPark mice.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, five additional antibodies (see Methods) directed against α-synuclein were not immunoreactive with the inclusions although they gave rise to expected α-synuclein-like immunoreactivity in nonaffected neurons.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“accompanied by formation of intraneuronal inclusions and dopamine nerve cell death.”
- Also stated in: § Results · plain
“a majority of them contained small cytoplasmic aggregates (Fig. 4A–D).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Results · plain
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In the paper
“We found many examples where a mitochondrial marker protein, the nucleus-encoded α-subunit of mitochondrial ATP synthase, partially overlapped with, was juxtaposed to, or even surrounded the inclusions (Fig. 4 E and F).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Decreased locomotion and reduced exploratory behavior first became apparent at age ≈14–15 weeks.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The absence of a functional α-synuclein gene had no obvious impact on the phenotype in MitoPark mice (data not shown).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Confocal and electron microscopy show that the inclusions contain both mitochondrial protein and membrane components.”
- Also stated in: § Results · hedged
“We found many examples where a mitochondrial marker protein, the nucleus-encoded α-subunit of mitochondrial ATP synthase, partially overlapped with, was juxtaposed to, or even surrounded the inclusions (Fig. 4 E and F).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Results · hedged
- It may state two separate claims as one. 13
- Probably not a substantial claim. 6
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unexpectedly, the inclusions also remained, and were immunoreactive with the h116–131 antibody in the MitoPark mice lacking a functional α-synuclein gene (data not shown).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Quantification of numbers of tyrosine hydroxylase (TH)-expressing midbrain neurons revealed a slow progressive cell loss, which was more marked and had an earlier onset in SN, which predominantly innervates dorsal striatum, in comparison with VTA, which predominantly innervates ventral striatum and cortical areas (Fig. 3 E–I).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Loss of DA innervation was first observed in dorsolateral striatum at age 12 weeks and this loss progressed to involve most of the dorsal and ventral striatum as the MitoPark mice became older (Fig. 3A–D).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The inclusions were present in most midbrain DA neurons (Fig. 4C) and their mean size increased as neurodegeneration progressed (Fig. 4D).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Some of these bodies had an amorphous content and a diffuse lining, whereas others displayed tubular formations and were surrounded by distinct double layer membranes (Fig. 5 B and C).”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In 6-week-old MitoPark mice, there was no observable DA cell loss (Fig. 3F) despite the presence of severely reduced mtDNA expression (Fig. 1E) in midbrain DA neurons.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus α-synuclein was neither needed for the PD phenotype nor the development of DA neuron inclusions in our mice.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: α-synuclein is commonly found in Lewy bodies in human PD.
In the paper
“Available data show that Lewy bodies can have a variety of morphological shapes (25), and it has been suggested that their morphology evolves with time (25).”
What the sources say
- Not checked yetcites [25] Shults CW. Proc Natl Acad Sci USA. 2006;103:1661–1668. doi: 10.1073/pnas.0509567103. [DOI] [PMC free article] [PubMed] [Google Scholar]
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The morphology of Lewy bodies has mainly been studied in brain tissue obtained from end-stage PD patients, and it is therefore not well established how these aggregates appear at early disease stages.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“We used in situ hybridizations (Fig. 1B) and mating to reporter mice (23), which activate the expression of β-galactosidase in cre-expressing cells (Fig. 1C), to establish that DAT-cre mice express cre mRNA and enzymatically active cre-recombinase protein in DA neurons of the midbrain.”
What the sources say
- Not checked yetcites [23] Soriano P. Nat Genet. 1999;21:70–71. doi: 10.1038/5007. [DOI] [PubMed] [Google Scholar]
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This differential degeneration is also characteristic of PD in man.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“It has recently been demonstrated that midbrain DA neurons of PD patients and elderly humans contain high levels of somatic mtDNA mutations, which may impair respiratory chain function.”
- Also stated in: § Abstract · boosted
“Analysis of mtDNA mutation levels in DA neurons with normal COX activity has demonstrated very high levels of mtDNA with deletions in both PD patients and aged controls and there was a linear increase of the mutation load with increasing age (7).”
What the sources say
- Not checked yetcites [7] Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, et al. Nat Genet. 2006;38:515–517. doi: 10.1038/ng1769. [DOI] [PubMed] [Google Scholar] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Abstract · boosted
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrate that respiratory chain deficiency in DA neurons in mice leads to characteristic manifestations of parkinsonism, including slowly progressive neuronal degeneration, typical behavioral disturbances, and the formation of intraneuronal inclusions.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In vitro studies have shown that α-synuclein can interact directly with lipids found in membranes (26, 27) and with proteins of the mitochondrial respiratory chain (28, 29).”
What the sources say
- Not checked yetcites [26] Cole NB, Murphy DD, Grider T, Rueter S, Brasaemle D, Nussbaum RL. J Biol Chem. 2002;277:6344–6352. doi: 10.1074/jbc.M108414200. [DOI] [PubMed] [Google Scholar]
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Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“TH-immunoreactive DA nerve cell body profiles were counted on coded slides at representative levels of SN and VTA, respectively, using two to five sections per animal and a total of 18 mice (nine littermate pairs, each consisting of one MitoPark and one control).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“The mitochondrial network has an elaborate system for protein degradation involving membrane bound AAA-proteases and LON protease in the matrix (31).”
What the sources say
- Not checked yetcites [31] Rugarli EI, Langer T. Trends Mol Med. 2006;12:262–269. doi: 10.1016/j.molmed.2006.04.002. [DOI] [PubMed] [Google Scholar]
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper relies on this without support.
Clinical studies have not established whether respiratory chain deficiency is a primary abnormality leading to inclusion formation and DA neuron death, or whether generalized metabolic abnormalities within degenerating DA neurons cause secondary damage to mitochondria.
“However, clinical studies have not established whether the respiratory chain deficiency is a primary abnormality leading to inclusion formation and DA neuron death, or whether generalized metabolic abnormalities within the degenerating DA neurons cause secondary damage to mitochondria.”
The paper relies on this without support.
α-synuclein is commonly found in Lewy bodies in human PD.
“However, we did not find evidence of α-synuclein in these inclusions, although α-synuclein is commonly found in Lewy bodies in human PD.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“For all the targeted cell types, TFAM depletion leads to mtDNA depletion (not reported for midbrain DA neurons), mitochondrial transcript depletion (not reported for midbrain DA neurons) and respiratory chain deficiency, suggesting that TFAM is essential for mtDNA maintenance in vivo”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Ekstrand et al., 2007
In the citing paper
“TFAM deletion in mouse pyramidal neurons causes mitochondrial late-onset neurodegeneration (MILON) (Sorensen et al., 2001) whereas deletion in mouse midbrain DA neurons leads to PD (Ekstrand et al., 2007).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Ekstrand et al., 2007
In the citing paper
“Alternative and more successful approaches to developing mouse models of mitochondrial disease involve manipulating the nuclear genes that regulate mtDNA maintenance and replication, such as TFAM [176][177][178][179][180][181][182], POLG ('Mutator' model) [183], and PEO1 (Twinkle; 'Deletor' model) [184].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [177]
Citations
Cites
Dauer, W., & Przedborski, S. (2003) · Neuron · doi:10.1016/s0896-6273(03)00568-3 · Cited by 5,469
Generalized lacZ expression with the ROSA26 Cre reporter strain
Soriano, P. (1999) · Nature Genetics · doi:10.1038/5007 · Cited by 5,237
Premature ageing in mice expressing defective mitochondrial DNA polymerase
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., et al. (2004) · Nature · doi:10.1038/nature02517 · Cited by 2,734
Self-citationDrosophila pink1 is required for mitochondrial function and interacts genetically with parkin
Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., Yoo, S. J., Hay, B. A., & Guo, M. (2006) · Nature · doi:10.1038/nature04779 · Cited by 1,788
Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin
Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., Bae, E., Kim, J., Shong, M., Kim, J.-M., et al. (2006) · Nature · doi:10.1038/nature04788 · Cited by 1,705
Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice
Larsson, N.-G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., & Clayton, D. A. (1998) · Nature Genetics · doi:10.1038/ng0398-231 · Cited by 1,594
Self-citationBender, A., Krishnan, K. J., Morris, C. M., Taylor, G. A., Reeve, A. K., Perry, R. H., Jaros, E., Hersheson, J. S., Betts, J., Klopstock, T., et al. (2006) · Nature Genetics · doi:10.1038/ng1769 · Cited by 1,570
Mitochondrial transcription factor A regulates mtDNA copy number in mammals
Ekstrand, M. I. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh109 · Cited by 919
Self-citationVolkow, N. D., Wang, G.-J., Fowler, J. S., Gatley, S. J., Logan, J., Ding, Y.-S., Hitzemann, R., & Pappas, N. (1998) · American Journal of Psychiatry · doi:10.1176/ajp.155.10.1325 · Cited by 885
Cabin, D. E., Shimazu, K., Murphy, D., Cole, N. B., Gottschalk, W., McIlwain, K. L., Orrison, B., Chen, A., Ellis, C. E., Paylor, R., et al. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-20-08797.2002 · Cited by 865
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- H Andersson, J Luthman, E Lindqvist, L Olson Neurotoxicology 16, 201–210 (1995).
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Metadata
- Authors
- Ekstrand, M. I., Terzioglu, M., Galter, D., Zhu, S., Hofstetter, C., Lindqvist, E., Thams, S., Bergstrand, A., Hansson, F. S., Trifunovic, A., Hoffer, B., Cullheim, S., Mohammed, A. H., Olson, L., & Larsson, N.-G.
- Affiliations
- Karolinska University Hospital (SE)
- Department of Laboratory Medicine and
- Karolinska Institutet (SE)
- National Institutes of Health (US)
- Corresponding author
- Larsson, Nils-Göran
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-01-23
- Volume
- 104
- Issue
- 4
- Pages
- 1325-1330
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1783140
- OpenAlex
- W2055557007
- Semantic Scholar
- eae41525f2f96b0fa42114d58d84dc3353e90137
- Cited by
- 605
- References
- 33
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 35 · 2023: 32 · 2022: 25 · 2021: 33 · 2020: 40 · 2019: 34 · 2018: 38 · 2017: 28 · 2016: 19 · 2015: 32 · 2014: 31 · 2013: 32 · 2012: 29
- FWCI
- 23.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- Karolinska Institutet
- Vetenskapsrådet
- Swedish Brain Power
- National Institutes of Health
- U.S. Public Health Service
- Parkinsonfonden
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, mitochondrial dysfunction, respiratory chain deficiency, dopaminergic neurons, midbrain, Lewy bodies, TFAM, mitochondrial DNA mutations, conditional knockout mice, parkinsonism, motor impairment, intraneuronal inclusions
- MeSH terms
- Animals, Base Sequence, Dopamine, Electron Transport, Immunohistochemistry, Microscopy, Electron, Neurons, DNA Probes, In Situ Hybridization, Parkinsonian Disorders, Mice
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