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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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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25 Own result · 11 Own interpretation · 8 Not checked yet · 1 Own method · 1 No basis given
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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).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“accompanied by formation of intraneuronal inclusions and dopamine nerve cell death.”
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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).”
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In the paper
“There was no increased embryonic or neonatal lethality in MitoPark mice.”
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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.”
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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).”
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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).”
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In the paper
“Decreased locomotion and reduced exploratory behavior first became apparent at age ≈14–15 weeks.”
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In the paper
“The absence of a functional α-synuclein gene had no obvious impact on the phenotype in MitoPark mice (data not shown).”
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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).”
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- It may state two separate claims as one. 13
- Probably not a substantial claim. 6
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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).”
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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).”
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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).”
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In the paper
“The inclusions were present in most midbrain DA neurons (Fig. 4C) and their mean size increased as neurodegeneration progressed (Fig. 4D).”
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“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).”
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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.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus α-synuclein was neither needed for the PD phenotype nor the development of DA neuron inclusions in our mice.”
plain- Asserted: passes — The authors put it forward as true.
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- 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]
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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.”
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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]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This differential degeneration is also characteristic of PD in man.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
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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.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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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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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).”
plainn = 18- Asserted: passes — The authors put it forward as true.
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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]
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
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BackgroundMitochondrial therapies for Parkinson's disease
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“This is significant because a conditional knockout of Tfam cause progressive loss of nigrostriatal dopaminergic neurons in mice.(34) Mitochondrial localization of PD associated gene DJ-1 and its ability to impact mitochondrial functions by modulating oxidative damage induced by mitochondrial toxins further enforces th…”
BackgroundReview: Central nervous system involvement in mitochondrial disease
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Lauritzen, K. H., Moldestad, O., Eide, L., Carlsen, H., Nesse, G., Storm, J. F., Mansuy, I. M., Bergersen, L. H., & Klungland, A. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01149-09 · Cited by 59
“Mouse models with respiratory chain deficient dopamine neurons have demonstrated adult onset Parkinsonism phenotype (16), and cell death induced by mitochondrial toxicity is likely to underlie Alzheimer disease (32).”
BackgroundLangley, M. R., Ghaisas, S., Ay, M., Luo, J. D., Palanisamy, B. N., Jin, H., Anantharam, V., Kanthasamy, A., & Kanthasamy, A. G. (2017) · NeuroToxicology · doi:10.1016/j.neuro.2017.06.002 · Cited by 61
“Although these aggregates did not contain a-synuclein, they did increase in size over time and partially colocalized with mitochondrial membrane proteins (Ekstrand et al., 2007).”
InfluentialPhillipson, O. T. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.09.006 · Cited by 60
Cross-talk between mitochondria and proteasome in Parkinson’s disease pathogenesis
Martins-Branco, D. A. (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00017 · Cited by 63
“, and Larsson, N. G. (2007). Progressive parkinsonism in mice with respiratorychain-deficient dopamine neurons.”
Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models
Airavaara, M., Parkkinen, I., Konovalova, J., Albert, K., Chmielarz, P., & Domanskyi, A. (2020) · Current Protocols in Neuroscience · doi:10.1002/cpns.88 · Cited by 61
“Several dopaminergic neuron-specific Cre recombinase expressing mouse lines (DAT-Cre) have also been created (Backman et al., 2006; Ekstrand et al., 2007; Turiault et al., 2007; Zhuang, Masson, Gingrich, Rayport, & Hen, 2005).”
BackgroundMethodInfluentialYeast as a model to study mitochondrial mechanisms in ageing
de Barros, M. H., da Cunha, F. M., de Oliveira, G. A., Tahara, E. B., & Kowaltowski, A. J. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.04.008 · Cited by 58
Mitochondrial preconditioning: a potential neuroprotective strategy
Correia, S. C. (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00138 · Cited by 58
El‐Ghazaly, M. A., Sadik, N. A. H., Rashed, E. R., & Abd-El-Fattah, A. A. (2013) · Toxicology and Industrial Health · doi:10.1177/0748233713487251 · Cited by 58
“The mechanism by which the inhibition of complex I leads to the degeneration of dopaminergic neurons involves the activation of mitochondrion-dependent apoptotic molecular pathways (Ekstrand et al., 2007; Waldmeier and Tatton, 2004).”
BackgroundChronic in vivo multi-circuit neurophysiological recordings in mice
Dzirasa, K., Fuentes, R., Kumar, S., Potes, J. M., & Nicolelis, M. A. L. (2010) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2010.11.014 · Cited by 59
Lysosomal function in macromolecular homeostasis and bioenergetics in Parkinson's disease
Schneider, L. E., & Zhang, J. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-14 · Cited by 59
“and associated intraneuronal inclusions [67].”
Mitochondrial dysfunction and biogenesis in the pathogenesis of Parkinson's disease.
Lin, T., Liou, C.-W., Chen, S., Chuang, Y., Tiao, M., Wang, P., Chen, J., & Chuang, J. (2009) · PubMed · Cited by 60
Mitochondrial dynamics and neuronal fate in Parkinson's disease
Santos, D., & Cardoso, S. M. (2012) · Mitochondrion · doi:10.1016/j.mito.2012.05.002 · Cited by 60
Lax, N., Turnbull, D. M., & Reeve, A. K. (2011) · The Neuroscientist · doi:10.1177/1073858411385469 · Cited by 80
Pomeranz, L. E., Ekstrand, M. I., Latcha, K. N., Smith, G. A., Enquist, L. W., & Friedman, J. M. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3193-16.2017 · Cited by 54
“DAT-Cre transgenic mice (Ekstrand et al., 2007) were kindly provided by N.-G. Larsson (Karolinska Institute, Solna, Sweden).”
BackgroundMethodSelf-citationNLRP3 inflammasomes: A potential target to improve mitochondrial biogenesis in Parkinson's disease
Khot, M., Sood, A., Tryphena, K. P., Khan, S. S., Srivastava, S., Singh, S. B., & Khatri, D. K. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175300 · Cited by 56
Gawęda-Walerych, K., Maruszak, A., Safranow, K., Białecka, M. A., Kłodowska-Duda, G. A., Czyźewski, K., Sławek, J. W., Rudzińska, M., Styczyńska, M., Opala, G., et al. (2008) · Journal of Neural Transmission · doi:10.1007/s00702-008-0121-9 · Cited by 53
“On the other hand, defects of nucleus-encoded, mtDNA transcription and replication machinery could contribute to parkinsonian phenotype (Baloh et al. 2007; Davidzon et al. 2006; Ekstrand et al. 2007; Luoma et al. 2004).”
BackgroundMisiak, M., Beyer, C., & Arnold, S. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.04.009 · Cited by 55
Rekaik, H., de Thé, F.-X. B., Prochiantz, A., Fuchs, J., & Joshi, R. L. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.10.002 · Cited by 54
“These mice present respiratory chain deficiencies and develop several features of PD, including progressive degeneration of the nigrostriatal system [48].”
Oxidative Modification and Its Implications for the Neurodegeneration of Parkinson’s Disease
Zhao, J., Yu, S., Zheng, Y., Yang, H., & Zhang, J. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9743-3 · Cited by 58
The protease Omi regulates mitochondrial biogenesis through the GSK3β/PGC-1α pathway
Xu, R., Hu, Q., Ma, Q., Liu, C., & Wang, G. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.328 · Cited by 54
“of mtDNA integrity or mitochondrial function may underlie neurodegenerative disorders.(35) Normally, mitochondrial biogenesis and function are dynamically regulated to adapt to the”
BackgroundA Proposed Circuit Computation in Basal Ganglia: History‐Dependent Gain
Yttri, E. A., & Dudman, J. T. (2018) · Movement Disorders · doi:10.1002/mds.27321 · Cited by 52
Ricke, K. M., Paß, T., Kimoloi, S., Fährmann, K., Jüngst, C., Schauss, A. C., Baris, O. R., Croon, M., Trifunović, A., Faelker, T. M. E., et al. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.1345-19.2019 · Cited by 57
“MitoPark mice (TfamloxP/loxP / Dat-cre) were bred as described previously (Ekstrand et al., 2007) and TfamloxP/WT or TfamloxP/loxP mice were used as controls.”
BackgroundMethodInfluentialSelf-citationMitochondrial DNA mutations and ageing
Greaves, L. C., & Turnbull, D. M. (2009) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2009.04.018 · Cited by 53
Transgenic rodent models of Parkinson’s disease
Harvey, B. K., Wang, Y., & Hoffer, B. J. (2009) · Acta neurochirurgica. Supplementum · doi:10.1007/978-3-211-78205-7_15 · Cited by 55
Self-citationSonogenetic-Based Neuromodulation for the Amelioration of Parkinson’s Disease
Fan, C., Wei, K., Chiu, N.-H., Liao, E., Wang, H., Wu, R., Ho, Y.-J., Chan, H., Wang, T. A., Huang, Y., et al. (2021) · Nano Letters · doi:10.1021/acs.nanolett.1c00886 · Cited by 53
Therapeutic targeting of mitophagy in Parkinson's disease
Masaldan, S., Callegari, S., & Dewson, G. (2022) · Biochemical Society Transactions · doi:10.1042/bst20211107 · Cited by 56
Castro, B. D., Pintado, C. O., García‐Flores, P., López‐Barneo, J., & Piruat, J. I. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00128-12 · Cited by 51
“Nonetheless, the 481 selective effect of this mitochondrial damage on SNpc cells, in comparison with 482 other neuronal types, has not been studied in detail (16).”
ResultMitochondrial turnover and homeostasis in ageing and neurodegeneration
Markaki, M., & Tavernarakis, N. (2020) · FEBS Letters · doi:10.1002/1873-3468.13802 · Cited by 50
Neurodegenerative signaling factors and mechanisms in Parkinson's pathology
Goswami, P., Joshi, N., & Singh, S. (2017) · Toxicology in Vitro · doi:10.1016/j.tiv.2017.06.008 · Cited by 51
Mitochondrial transcription factor A variants and the risk of Parkinson's disease
Gawęda-Walerych, K., Safranow, K., Maruszak, A., Białecka, M. A., Kłodowska-Duda, G. A., Czyźewski, K., Sławek, J. W., Rudzińska, M., Styczyńska, M., Opala, G., et al. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.11.037 · Cited by 51
Subcellular and regional localization of mRNA translation in midbrain dopamine neurons
Hobson, B. D., Kong, L., Angelo, M. F., Lieberman, O. J., Mosharov, E. V., Herzog, É., Sulzer, D., & Sims, P. A. (2022) · Cell Reports · doi:10.1016/j.celrep.2021.110208 · Cited by 49
“Recent work showed that another DAT-Cre line (Ekstrand et al., 2007) drove off-target expression in multiple regions outside the midbrain, including the bed nucleus of stria terminalis (BNST) and the lateral septum (LS) (Papathanou et al.”
Ghaisas, S., Langley, M. R., Palanisamy, B. N., Dutta, S., Kirthi, N., Plummer, P. J., Sarkar, S., Ay, M., Jin, H., Anantharam, V., et al. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.09.004 · Cited by 49
“Other groups have shown the development of nonmotor symptoms such as changes in circadian rhythm as well as anxiety or depression in the MP mouse model (Ekstrand et al., 2007; Galter et al., 2010).”
BackgroundResultInfluentialLin, T., Lin, K.-J., Lin, H., Lin, K.-L., Lan, M., Wang, P., Wang, T., Wang, F., Tsai, P.-C., Liou, C., et al. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.697440 · Cited by 50
“Oxidative stress is also shown to contribute to the cascade leading to nigrostriatal dopaminergic neurodegeneration in PD (Desai et al., 1996; Ekstrand et al., 2007; Dias et al., 2013).”
BackgroundBelin, A. C., Björk, B. F., Westerlund, M., Galter, D., Sydow, O., Lind, C., Pernold, K., Rosvall, L., Håkansson, A., Winblad, B., et al. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2007.05.010 · Cited by 48
Borroto‐Escuela, D. O., & Fuxé, K. (2019) · Journal of Neural Transmission · doi:10.1007/s00702-019-01969-2 · Cited by 50
Parkinson's disease: Exit toxins, enter genetics
Westerlund, M., Hoffer, B. J., & Olson, L. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.11.001 · Cited by 48
“Interestingly, these mice show several parkinsonian features including a progressive loss of dopamine neurons in substantia nigra, reduced striatal dopamine levels, reduced locomotor activity and formation of intracellular aggregates, and the mice die prematurely (Ekstrand et al., 2007).”
BackgroundInfluentialSelf-citationGoldberg, N. R. S., Haack, A. K., Lim, N. S., Janson, O. K., & Meshul, C. K. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.02.027 · Cited by 49
McMeekin, L. J., Fox, S. N., Boas, S. M., & Cowell, R. M. (2021) · Cells · doi:10.3390/cells10020352 · Cited by 53
Mitochondrial protein dysfunction in pathogenesis of neurological diseases
Wang, L., Yang, Z., He, X., Pu, S., Yang, C., Wu, Q., Zhou, Z., Cen, X., & Zhao, H. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.974480 · Cited by 48
“The central importance of mitochondrial proteins has been widely highlighted by the association of aberrant mitochondrial protein expression (Lin et al., 2004; Ekstrand et al., 2007; Tysnes and Storstein, 2017), localization (Gandhi, 2006; Lu and Guo, 2020), folding, and function (Castro et al.”
BackgroundMitochondria-mediated damage to dopaminergic neurons in Parkinson's disease (Review)
Liu, X., Wang, Y., Yu, X., Li, D., & Li, G. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3255 · Cited by 45
“…in nigral dopaminergic neurons of aged individuals and sporadic PD subjects (106-108). knockout of the mtDNA transcription gene inhibits the expression of mtDNA and the activities in the respiratory chain of dopaminergic neurons, accompanied with progressive parkin-sonism in mouse models (109).”
Boyalla, S. S., Victor, M. B., Roemgens, A., Beyer, C., & Arnold, S. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22669 · Cited by 45
“…mitochondrial DNA transcription by ablation of the mitochondrial transcription factor A (TFAM) in nigrostriatal dopaminergic neurons caused a progressive loss of dopaminergic neurons resulting from reduced mitochondrial DNA expression and respiratory chain deficiency (Ekstrand et al., 2007).”
BackgroundStrategic Role for Mitochondria in Alzheimer's Disease and Cancer
Hedskog, L., Zhang, S., & Ankarcrona, M. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4259 · Cited by 45
Zhang, Y., Granholm, A.-C., Huh, K. H., Shan, L., Dı́az-Ruiz, O., Malik, N., Olson, L., Hoffer, B. J., Lupica, C. R., Hoffman, A. F., et al. (2012) · Brain · doi:10.1093/brain/aws196 · Cited by 45
“To examine whether Akt activation can protect vulnerable dopamine neurons after transplantation, we grafted ventral mesencephalic embryonic tissue from conditional DA-PTEN-KO and control mice bilaterally into the dopamine depleted striata of MitoPark mice (Ekstrand et al., 2007; Harvey et al., 2008; Ekstrand and Galte…”
BackgroundMethodResultInfluentialSelf-citationPapathanou, M., Dumas, S., Pettersson, H. I., Olson, L., & Wallén‐Mackenzie, Å. (2019) · eNeuro · doi:10.1523/eneuro.0198-19.2019 · Cited by 45
Self-citationFeng, S., Wang, Z., Yuan, Y., Sun, H., Chen, N., & Zhang, Y. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14699 · Cited by 47
“A study conducted in Mito-Park mice, which have reduced mitochondrial DNA expression and replicate the major pathophysiological changes in PD, demonstrated that mitochondrial DNA deletions are involved in the formation of Lewy bodies harboring α-Syn, possibly by initiating a process of aggregation of redundant protein…”
BackgroundBarber‐Singh, J., Seo, B. B., Nakamaru‐Ogiso, E., Lau, Y., Matsuno‐Yagi, A., & Yagi, T. (2009) · Rejuvenation Research · doi:10.1089/rej.2009.0854 · Cited by 45
De, R., Mazumder, S., & Bandyopadhyay, U. (2020) · Cell Biology and Toxicology · doi:10.1007/s10565-020-09561-1 · Cited by 47
Palin, E., Paetau, A. E., & Suomalainen, A. (2013) · Brain · doi:10.1093/brain/awt160 · Cited by 46
“…perturbed mitochondrial quality control is suggested to contribute to pathology (Greene et al., 2003; Clark et al., 2006; Park et al., 2006; Ekstrand et al., 2007; Narendra et al., 2008, 2010; Vives-Bauza et al., 2010), but this mechanism has been Table 3 Immunoreactivity of mitochondrial…”
Cre-driven optogenetics in the heterogeneous genetic panorama of the VTA
Pupe, S., & Wallén‐Mackenzie, Å. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.04.005 · Cited by 44
Chen, C., Li, X., Ge, G., Liu, J., Biju, K. C., Laing, S. D., Qian, Y., Ballard, C., He, Z., Masliah, E., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-23795-4 · Cited by 44
Genetically engineered animal models of Parkinson's disease: From worm to rodent
Breger, L. S., & Armentero, M. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14300 · Cited by 45
Glutamate homeostasis and dopamine signaling: Implications for psychostimulant addiction behavior
Fischer, K. D., Knackstedt, L. A., & Rosenberg, P. A. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104896 · Cited by 42
“, 2005) whereas the DAT-Cre driver utilized by Papathanou and colleagues is a 5’UTR transgenic (Ekstrand et al., 2007; Papathanou et al., 2018).”
BackgroundMethodInfluentialVoltage-gated calcium channels and Parkinson's disease
Hurley, M. J., & Dexter, D. T. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.11.006 · Cited by 46
Advances in animal models of Parkinson's disease
He, S., Ru, Q., Chen, L., Xu, G., & Wu, Y. (2024) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2024.111024 · Cited by 54
“(Ekstrand et al., 2007), and have study also found that DA neurons in MitoPark mice degenerated at 16 weeks of age, and the degeneration was severe at about 27 weeks of age (Lynch et al., 2018).”
Bulteau, A., Mena, N. P., Auchère, F., Lee, I., Prigent, A., Lobsiger, C. S., Camadro, J., & Hirsch, É. C. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.03.036 · Cited by 41
Cao, Q., Luo, S., Yao, W., Qu, Y., Wang, N., Hong, J., Murayama, S., Zhang, Z., Chen, J., Hashimoto, K., et al. (2022) · Molecular Therapy - Nucleic Acids · doi:10.1016/j.omtn.2022.05.037 · Cited by 41
“The previous study has shown that the a-Syn knockout (KO) mice did exhibit abnormalities in synaptic morphology and function, along with fairly subtle behavioral changes.(46,47) The a-Syn-HDO is widely distributed throughout the brain by ICV injection.”
BackgroundKupsch, A. R., Schmidt, W., Gizatullina, Z. Z., Dębska–Vielhaber, G., Voges, J., Striggow, F., Panther, P., Schwegler, H., Heinze, H., Vielhaber, S., et al. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1185-3 · Cited by 42
Time-dependent assessment of stimulus-evoked regional dopamine release
Lippert, R. N., Cremer, A. L., Thanarajah, S. E., Korn, C., Jahans-Price, T., Burgeno, L. M., Tittgemeyer, M., Brüning, J. C., Walton, M. E., & Backes, H. (2019) · Nature Communications · doi:10.1038/s41467-018-08143-4 · Cited by 42
Damage in Mitochondrial DNA Associated with Parkinson's Disease
Martín-Jiménez, R., Lurette, O., & Hébert-Chatelain, É. (2020) · DNA and Cell Biology · doi:10.1089/dna.2020.5398 · Cited by 40
“Indeed, conditional knockout of TFAM in DA neurons in MitoPark mice leads to low levels of mtDNA, and progressive loss of DA neurons (Ekstrand et al. , 2007).”
Tsai, K., Cheng, Y., Leu, H., Lee, Y., Chen, T., Liu, D.-H., & Kao, C.-L. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.05.012 · Cited by 40
“These mice present with reduced mitochondrial DNA expression, mitigated function of the mitochondrial respiratory chain in dopaminergic neurons of the substantia nigra, behavioral abnormalities, and dopamine depletion in the striatum (Ekstrand et al., 2007).”
Ding, S., Li, L., & Zhou, F.-M. (2014) · Journal of Neurophysiology · doi:10.1152/jn.00752.2014 · Cited by 40
Papathanou, M., Creed, M. C., Dorst, M. C., Bimpisidis, Z., Dumas, S., Pettersson, H. I., Bellone, C., Silberberg, G., Lüscher, C., & Wallén‐Mackenzie, Å. (2018) · Frontiers in Neural Circuits · doi:10.3389/fncir.2018.00064 · Cited by 40
Lrrk2 and α-synuclein are co-regulated in rodent striatum
Westerlund, M., Ran, C., Borgkvist, A., Sterky, F. H., Lindqvist, E., Lundströmer, K., Pernold, K., Brené, S., Kallunki, P., Fisone, G., et al. (2008) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2008.08.001 · Cited by 40
Self-citationSong, L., Shan, Y., Lloyd, K. C. K., & Cortopassi, G. A. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds365 · Cited by 39
“Mitochondrial integrity plays an important role in mitochondrial respiratory function, other studies indicated that the defects of mitochondrial transcripts markedly reduced mitochondrial respiratory function in DA and precipitated a parkinsonian phenotype in MitoPark mice (25).”
BackgroundTransgenic animal models of neurodegeneration based on human genetic studies
Harvey, B. K., Richie, C. T., Hoffer, B. J., & Airavaara, M. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0476-6 · Cited by 38
“HEK-293T cells transfected with the R1441C/G mutant of LRRK2 had decreased GTPase activity compared to non-mutant LRRK2 (Ekstrand et al. 2007).”
Self-citationRuud, J., Alber, J., Tokarska, A., Engström, L., Nolte, H., Biglari, N., Lippert, R. N., Lautenschlager, Ä., Cieślak, P. E., Szumiec, Ł., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.037 · Cited by 42
Mitochondrial dysfunction–induced H3K27 hyperacetylation perturbs enhancers in Parkinson’s disease
Huang, M., Lou, D. W., Charli, A., Kong, D., Jin, H., Zenitsky, G. D., Anantharam, V., Kanthasamy, A., Wang, Z., & Kanthasamy, A. G. (2021) · JCI Insight · doi:10.1172/jci.insight.138088 · Cited by 45
“MP Tg mice were a gift from Nils-Goran Larsson at the Karolinska Institute in Stockholm (87, 88), and were originally generated in his laboratory at the Max Planck Institute for Biology of Ageing by conditionally knocking out TFAM through control of the dopamine transporter (DAT), as previously described.”
MethodFox, S. N., McMeekin, L. J., Savage, C. H., Joyce, K. L., Boas, S. M., Simmons, M. S., Farmer, C. B., Ryan, J., Pereboeva, L., Becker, K., et al. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00369-w · Cited by 36
Therapeutic effects of phlorotannins in the treatment of neurodegenerative disorders
Kwon, S. Y., Kwon, O. I., Hwang, H. J., Shin, H., & Yang, S. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1193590 · Cited by 43
Impaired mitochondrial homeostasis and neurodegeneration: towards new therapeutic targets?
Corona, J. C., & Duchen, M. R. (2014) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-014-9576-6 · Cited by 38
“In a conditional knockout mouse with disruption of the gene for mtTFA, mtDNA expression and respiratory chain deficiency were reduced in dopaminergic neurons (Ekstrand et al. 2007).”
BackgroundBérubé‐Carrière, N., Guay, G., Fortin, G. M., Kullander, K., Olson, L., Wallén‐Mackenzie, Å., Trudeau, L., & Descarries, L. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.07992.x · Cited by 37
“…transgenic mice in which Cre was specifically expressed in cells expressing the DA transporter DAT (DAT-Cre of mixed C57BL ⁄ 6 ⁄ J and Sv129 background; Ekstrand et al., 2007) were mated with Vglut2f ⁄ f mice (mixed C57BL ⁄ 6 ⁄ J and Sv129 background; Wallén-Mackenzie et al., 2006), and the…”
MethodInfluentialSelf-citationReinforcing mitochondrial functions in aging brain: An insight into Parkinson's disease therapeutics
Chandra, G., Shenoi, R. A., Anand, R., Rajamma, U., & Mohanakumar, K. P. (2017) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2017.12.004 · Cited by 39
Foxa2: The Rise and Fall of Dopamine Neurons
Arenas, E. (2008) · Cell stem cell · doi:10.1016/j.stem.2008.01.012 · Cited by 38
Torraco, A., Díaz, F., Vempati, U. D., & Moraes, C. T. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.06.003 · Cited by 38
Bimpisidis, Z., König, N., Stagkourakis, S., Zell, V., Vlcek, B., Dumas, S., Giros, B., Broberger, C., Hnasko, T. S., & Wallén-Mackenzie, Å. (2019) · eNeuro · doi:10.1523/eneuro.0066-19.2019 · Cited by 36
“DAT-Cre (Ekstrand et al., 2007), Vglut2-Cre (Borgius et al., 2010), Calb2-Cre (The Jackson Laboratory, RRID:MGI_4365741), and NeuroD6-Cre/NEX-Cre (Goebbels et al., 2006) transgenic mice were bred with C57BL/6N Tac wild-type mice (Taconic) for optogenetics-based experiments.”
MethodZhu, M., Li, X., Tian, X., & Wu, C. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv081 · Cited by 39
“Mice that lack a mitochondrial protein TFAM in midbrain DA neurons develop progressive Parkinsonism (12).”
BackgroundMitochondrial dysfunction in Parkinson’s disease
Hattori, N., & Sato, S. (2024) · Journal of Neural Transmission · doi:10.1007/s00702-024-02863-2 · Cited by 41
“…there remains a significant gap in our understanding of the molecular events that lead to mitochondrial dysfunctions, their effects on mtDNA, and how mtDNA damage can further contribute to the development and progression of PD, ultimately resulting in its clinical symptoms (Ekstrand et al. 2007).”
Hedlund, E., Belnoue, L., Theofilopoulos, S., Saltó, C., Bye, C. R., Parish, C. L., Deng, Q., Kadkhodaei, B., Ericson, J., Arenas, E., et al. (2016) · Scientific Reports · doi:10.1038/srep26448 · Cited by 37
Baptista, M. A. S., Dave, K. D., Sheth, N. P., Silva, S. N. D., Carlson, K. M., Aziz, Y. N., Fiske, B. K., Sherer, T., & Frasier, M. A. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.011940 · Cited by 37
“As an outcome, MJFF launched an initiative to generate or characterize genetic and toxin models of PD, and funded seven rodent model projects (Cannon et al., 2013; Daher et al., 2009; Ekstrand et al., 2007; Frank-Cannon et al., 2008; Kuo et al., 2010; Sotiriou et al., 2010; Tong et al., 2009).”
Warren, E. B., Aicher, A., Fessel, J. P., & Konradi, C. L. (2017) · PLoS ONE · doi:10.1371/journal.pone.0190456 · Cited by 36
Long term rapamycin treatment improves mitochondrial DNA quality in aging mice
Bielas, J. H., Herbst, A. J., Widjaja, K., Hui, J., Aiken, J. M., McKenzie, D. I., Miller, R. A., Brooks, S. V., & Wanagat, J. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.02.021 · Cited by 38
“detected in the brain, heart, kidney, and skeletal muscle of aged mammals and in the mitochondrial mutator mice.(Wanagat et al., 2001; Ekstrand et al., 2007; McKiernan et al., 2007; Baris et al., 2015).”
BackgroundNovel Targets for Parkinson’s Disease: Addressing Different Therapeutic Paradigms and Conundrums
Rane, P., Sarmah, D., Bhute, S., Kaur, H., Goswami, A., Kalia, K., Borah, A., Dave, K. R., Sharma, N., & Bhattacharya, P. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00180 · Cited by 35
The PPARGC1A locus and CNS-specific PGC-1α isoforms are associated with Parkinson's Disease
Soyal, S. M., Zara, G., Ferger, B., Felder, T. K., Kwik, M., Nofziger, C., Dossena, S., Schwienbacher, C., Hicks, A. A., Pramstaller, P. P., et al. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.09.016 · Cited by 36
Modified level of miR‐376a is associated with Parkinson's disease
Baghi, M., Delavar, M. R., Yadegari, E., et al. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14979 · Cited by 36
Selective Neuron Vulnerability in Common and Rare Diseases—Mitochondria in the Focus
Paß, T., Wiesner, R. J., & Pla‐Martín, D. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.676187 · Cited by 37
“These so called “MitoPark” animals showed rapid and selective loss of dopaminergic neurons in the SNc due to mtDNA depletion, which was accompanied by progressive motor impairment (Ekstrand et al., 2007).”
BackgroundThe Role of Oxidative Stress in Neurodegenerative Diseases
Ksiazek-Winiarek, D. J., & Glabinski, A. R. (2014) · Oxidative stress in applied basic research and clinical practice · doi:10.1007/978-1-4939-0440-2_8 · Cited by 36
Physiological and pathological functions of LRRK2: implications from substrate proteins
Araki, M., Ito, G., & Tomita, T. (2018) · Neuronal Signaling · doi:10.1042/ns20180005 · Cited by 37
Parkinson Disease: Translating Insights from Molecular Mechanisms to Neuroprotection
Pirooznia, S. K., Rosenthal, L. S., Dawson, V. L., & Dawson, T. M. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000189 · Cited by 36
Masi, A., Narducci, R., Resta, F., Carbone, C., Kobayashi, K., & Mannaioni, G. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.13066 · Cited by 33
“A very relevant piece of evidence in this respect is the reduction in Ih current density reported in SNc DA neurons from MitoPark mice, a transgenic model in which a mitochondrial mutation leads to parkinsonism with preferential nigrostriatal degeneration (Ekstrand et al., 2007; Good et al., 2011).”
BackgroundLahti, L., Peltopuro, P., Piepponen, T. P., & Partanen, J. (2012) · Development · doi:10.1242/dev.071936 · Cited by 34
“Neither DATCre;Fgfr1cko;Fgfr2cko nor ThCre;Fgfr1cko;Fgfr2cko mutants displayed obvious alterations in their midbrain DA neurons or behavior, although controlled behavioral testing may reveal more subtle deficiencies.”
BackgroundInfluential
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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