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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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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).”
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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).”
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
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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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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).”
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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.”
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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.”
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]
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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.”
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]
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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.”
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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).”
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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]
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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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Self-citationDrosophila pink1 is required for mitochondrial function and interacts genetically with parkin
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Mitochondrial transcription factor A regulates mtDNA copy number in mammals
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“Indeed, the inclusions found in dopaminergic neurons have no α-syn but rather, abnormal mitochondrial membranes [126].”
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“Interestingly, the mitochondrial transcription factor A protein (Tfam), whose expression sequence is part of the promoters within the D-loop region of mtDNA, have been implicated in PD [173].”
BackgroundMitochondrial alterations in Parkinson’s disease: new clues
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“MitoPark mice were created by selective inactivation of mitochondrial transcription factor A (TFAM) in the nigrostriatal pathway (22).”
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Targeting mitophagy in Parkinson's disease
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Mitochondrial DNA: Impacting Central and Peripheral Nervous Systems
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“These mouse models show features not only of mitochondrial diseases, but also of ageing (Trifunovic et al., 2004) and age-related neurodegenerative disorders such as Parkinson disease (Ekstrand et al., 2007).”
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“, 2011), axonal degeneration was related to cell body loss (Ekstrand et al., 2007).”
InfluentialVGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation
Birgner, C., Nordenankar, K., Lundblad, M., Méndez, J. A. T., Smith, C., Grevès, M. L., Galter, D., Olson, L., Fredriksson, A., Trudeau, L., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910986107 · Cited by 119
“We produced such a conditional knockout by crossing our Vglut2 mice, generated and validated previously in our laboratory (10, 12), with transgenic DAT-Cre mice (16).”
BackgroundMethodSelf-citationParkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up?
Grenier, K., McLelland, G., & Fon, E. A. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00100 · Cited by 124
“To overcome the limitations of in vitro neuronal cultures, Sterky and colleagues crossed MitoPark mice – which develop progressive parkinsonism and mitochondrial abnormalities stemming from the ablated expression of mitochondrial transcription factor A in dopaminergic neurons (85) – with parkin knockout mice.”
BackgroundAnimal Models of Parkinson’s Disease
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Animal models of Parkinson's disease: An updated overview
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Physiological Phenotype and Vulnerability in Parkinson's DiseasePreprint
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“DA neurons of SNc depend on mitochondrial DNA for survival (Ekstrand et al. 2007), so the accumulation of these mutations can potentially lead to the development of a bioenergetic deficiency that becomes lethal over time.”
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“MitoPark mice were developed by inactivating the mitochondrial transcription factor A (TFAM) in dopaminergic neurons (31) to model the mitochondrial dysfunction exhibited by the progressively neurodegenerative Parkinsonian syndrome, with its diverse spectrum of motor and nonmotor symptoms.”
MethodAnalysis of dopamine transporter gene expression pattern − generation of DAT‐iCre transgenic mice
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Ross, J. M., Olson, L., & Coppotelli, G. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160819458 · Cited by 113
“correlation between mitochondrial dysfunction and PD, and mouse models mimicking the disease have been generated by genetically impairing mitochondrial function in dopaminergic neurons [114] or by using toxins that affect mitochondria, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [115].”
BackgroundSelf-citationGuo, J., Li, Z., Liu, W., Wang, X., Wang, Z., Wang, Z., French, A. J., Kang, D., Chen, L., Thibodeau, S. N., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-3482 · Cited by 116
“Moreover, the depletion of mtDNA and reduction of TFAM-dependent mtDNA expression are involved in infantile mitochondrial myopathy, Alzheimer disease, and Parkinson disease (13, 15, 16).”
Parkinson’s disease: experimental models and reality
Jiang, P., & Dickson, D. W. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1788-5 · Cited by 116
“A mouse model with significant mitochondrial dysfunction— MitoPark—was generated by disruption of TFAM in dopaminergic neurons [49].”
Mitochondrial DNA mutations and aging: devils in the details?
Khrapko, K., & Vijg, J. (2009) · Trends in Genetics · doi:10.1016/j.tig.2008.11.007 · Cited by 112
MitoPark mice mirror the slow progression of key symptoms and L‐DOPA response in Parkinson's disease
Galter, D., Pernold, K., Yoshitake, T., Lindqvist, E., Hoffer, B. J., Kehr, J., Larsson, N., & Olson, L. (2009) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2009.00542.x · Cited by 112
“To model severe mitochondrial dysfunction specifically in dopamine (DA) neurons, a mouse has been developed in which the mitochondrial transcription factor Tfam is selectively removed in DA neurons using the Cre-loxP system (Ekstrand et al. 2007).”
MethodSelf-citationParkinson's disease: a model dilemma
Beal, M. F. (2010) · Nature · doi:10.1038/466s8a · Cited by 114
Mitochondria: A Therapeutic Target for Parkinson’s Disease?
Luo, Y., Hoffer, A., Hoffer, B. J., & Qi, X. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160920704 · Cited by 108
“Directed deletion of transcriptional factor A (TFAM) in mouse DA neurons using the Cre-LoxP system, termed as MitoPark mice, causes marked deletion of mtDNA, severe impairment of oxidative phosphorylation and slowly progressive motor deficits in the DA system that mimic human parkinsonism as well as altered response t…”
MethodSelf-citationRegulation of common neurological disorders by gut microbial metabolites
Park, J., & Kim, C. H. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00703-x · Cited by 126
Sleep and circadian rhythms in Parkinson’s disease and preclinical models
Hunt, J., Coulson, E. J., Rajnarayanan, R. V., Oster, H., Videnović, A., & Rawashdeh, O. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00504-w · Cited by 118
“Termed the ‘MitoPark’ model [261], these mice also recapitulate the”
BackgroundZhu, J., Gusdon, A. M., Çimen, H., Houten, B. V., Koç, E., & Chu, C. T. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.46 · Cited by 109
Polyunsaturated Fatty Acids Induce α-Synuclein-Related Pathogenic Changes in Neuronal Cells
Assayag, K., Yakunin, E., Loeb, V., Selkoe, D. J., & Sharon, R. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.070373 · Cited by 109
Animal Models of Parkinson's Disease: A Gateway to Therapeutics?
Le, W., Sayana, P., & Jankovic, J. J. (2013) · Neurotherapeutics · doi:10.1007/s13311-013-0234-1 · Cited by 114
“Conditional disruption of the gene for mitochondrial transcription factor A in DA neurons named MitoPark results in a parkinsonism phenotype in mice with adult-onset of slowly progressive impairment of motor function, and intraneuronal inclusions and DA neuron degeneration [102].”
BackgroundMethodThe Centrality of Mitochondria in the Pathogenesis and Treatment of Parkinson's Disease
Camilleri, A., & Vassallo, N. (2014) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12264 · Cited by 106
“These mice develop a progressive motor phenotype associated with loss of midbrain dopamine neurons [111,112].”
BackgroundProteasome inhibition modeling nigral neuron degeneration in Parkinson’s disease
Xie, W., Li, X., Li, C., Zhu, W., Jankovic, J. J., & Le, W. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06914.x · Cited by 105
Mouse models of mitochondrial DNA defects and their relevance for human disease
Tyynismaa, H., & Suomalainen, A. (2009) · EMBO Reports · doi:10.1038/embor.2008.242 · Cited by 105
“Tissue-specific TFAM knockouts are good models of respiratory-chain dysfunction at stages in which mtDNA is still present in reduced amounts.”
BackgroundInfluentialMitochondrial DNA, base excision repair and neurodegeneration
de Souza-Pinto, N. C., Wilson, D. M., Stevnsner, T., & Bohr, V. A. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.03.011 · Cited by 102
Mitochondrial Dysfunction and Oxidative Stress in Parkinson’s Disease
Onyango, I. G. (2007) · Neurochemical Research · doi:10.1007/s11064-007-9482-y · Cited by 100
Poul, E. L., Boléa, C., Girard, F., Poli, S. M., Charvin, D., Campo, B., Chapalay, J. B., Bessif, A., Luo, B., Koser, A. J., et al. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.196063 · Cited by 103
Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases
Bartman, S., Coppotelli, G., & Ross, J. M. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46030130 · Cited by 110
“The MitoPark mouse is a transgenic model utilized in studying PD and includes the selective removal of the mitochondrial transcription factor, TFAM, from midbrain dopaminergic neurons, resulting in severe mitochondrial respiratory defects and ultimately cell death [230].”
BackgroundMethodFernández-Checa, J. C., Fernandez, A., Morales, A., Marí, M., García‐Ruiz, C., & Colell, A. (2010) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152710791556113 · Cited by 99
“for the hypothesis that acquired respiratory chain dysfunction may be of pathophysiological importance in PD [145].”
BackgroundInflammation in transgenic mouse models of neurodegenerative disorders
Schwab, C., Klegeris, A., & McGeer, P. L. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.10.013 · Cited by 97
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“For example, mitochondrial dysfunction in neuronal tissues has been associated with epilepsy [2] as well as neurodegenerative disorders and ageing [3,4].”
BackgroundGordon, R., Neal, M. P., Luo, J. D., Langley, M. R., Harischandra, D. S., Panicker, N., Charli, A., Jin, H., Anantharam, V., Woodruff, T. M., et al. (2016) · Nature Communications · doi:10.1038/ncomms12932 · Cited by 102
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Self-citationMitochondrial DNA damage triggers spread of Parkinson’s disease-like pathology
Tresse, E., Marturia-Navarro, J., Sew, W. Q. G., Cisquella-Serra, M., Jaberi, E., Riera-Ponsati, L., Fauerby, N., Hu, E., Kretz, O., Aznar, S., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02251-4 · Cited by 99
“Nevertheless, strong evidence from PD animal models supports the involvement of mitochondrial disturbances including mtDNA packaging [21].”
BackgroundMitochondrial Dysfunction in Genetic Animal Models of Parkinson's Disease
Trancikova, A. K., Tsika, E., & Moore, D. J. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4200 · Cited by 94
“Further, MitoPark mice successfully recapitulate some key aspects of PD-related pathology, including progressive, adult-onset dopaminergic neurodegeneration accompanied by levodopa-responsive motor deficits, and the formation of intraneuronal mitochondrial aggregates (40).”
InfluentialCurrent perspective of mitochondrial biology in Parkinson's disease
Kaidery, N. A., & Thomas, B. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.03.001 · Cited by 95
Fiebig, C., Keiner, S., Ebert, B. M., Schäffner, I., Jagasia, R., Lie, D., & Beckervordersandforth, R. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00040 · Cited by 85
“Because of the long half-life of Tfam transcripts conditional Tfam mutants consistently show protracted development of a phenotype after disruption of the Tfam locus (Wang et al., 1999; Sorensen et al., 2001; Ekstrand et al., 2007; Beckervordersandforth et al., 2017).”
BackgroundKondadi, A. K., Anand, R., & Reichert, A. S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174311 · Cited by 94
“These mitochondria exhibited abnormal mitochondrial membranes with vacuolization in some cases [92].”
BackgroundThe ageing mitochondrial genome
Krishnan, K. J., Greaves, L. C., Reeve, A. K., & Turnbull, D. M. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm635 · Cited by 89
“However, mtDNA dysfunction resulting from reduced mtDNA expression has been shown to cause a parkinsonian phenotype in mice (35).”
BackgroundMitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD
Esteves, A. R., Arduíno, D. M., Silva, D. F., Oliveira, C. R., & Cardoso, S. M. (2011) · Parkinson s Disease · doi:10.4061/2011/693761 · Cited by 90
“The most compelling evidence regarding TFAM involvement in PD was reported by Ekstrand and colleagues showing that the conditional and selective inactivation of both TFAM alleles in substantia nigra of transgenic mice induced respiratory chain deficiency in dopaminergic neurons leading to a Parkinsonism phenotype with…”
Pathophysiological Features of Nigral Dopaminergic Neurons in Animal Models of Parkinson’s Disease
Guatteo, E., Berretta, N., Monda, V., Ledonne, A., & Mercuri, N. B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094508 · Cited by 91
Alsiö, J., Nordenankar, K., Arvidsson, E., Birgner, C., Mahmoudi, S., Halbout, B., Smith, C., Fortin, G. M., Olson, L., Descarries, L., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2397-11.2011 · Cited by 92
“By crossing Vglut2f/f mice (Wallén-Mackenzie et al., 2006; WallénMackenzie et al., 2009) with DAT-Cre mice (Ekstrand et al., 2007), as described previously (Birgner et al., 2010), both Vglut2f/f;DAT-Cre cKO and Vglut2f/f control (Ctrl) mice (which do not express the DAT-Cre transgene and…”
BackgroundMethodSelf-citationMitochondrial Gene Therapy Augments Mitochondrial Physiology in a Parkinson's Disease Cell Model
Keeney, P. M., Quigley, C. K., Dunham, L. D., Papageorge, C. M., Iyer, S., Thomas, R. R., Schwarz, K. M., Trimmer, P. A., Khan, S. M., Portell, F. R., et al. (2009) · Human Gene Therapy · doi:10.1089/hum.2009.023 · Cited by 88
“…there are no animal models of sporadic PD that produce specific alterations of mtDNA beyond the TFAM conditional knockout model (‘‘MitoPark’’) that produces selective mtDNA depletion in and progressive death of dopaminergic nigral neurons through bioenergetic deficiency (Ekstrand et al., 2007).”
BackgroundFuentes, R., Petersson, P., & Nicolelis, M. A. L. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07417.x · Cited by 85
“, 2006); genetically targeted dopaminergic mitochondrial injury (Ekstrand et al., 2007); transgenic or viral vectorinduced overexpression of a-synuclein (Masliah et al.”
BackgroundPGC-1s in the Spotlight with Parkinson’s Disease
Piccinin, E., Sardanelli, A. M., Seibel, P., Moschetta, A., Cocco, T., & Villani, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073487 · Cited by 85
“The discovery of dominantlyinherited, late-onset Parkinsonism has recently been linked to a missense mutation in VPS35 which implicates retromer dysfunction in the pathogenesis of PD [76,77].”
BackgroundExperimental models of Parkinson's disease: Challenges and Opportunities
Lal, R., Singh, A., watts, S., & Chopra, K. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176819 · Cited by 94
Singh, S., Mishra, A., Mohanbhai, S. J., Tiwari, V., Chaturvedi, R. K., Khurana, S., & Shukla, S. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.08.033 · Cited by 82
Brain Mitochondria, Aging, and Parkinson’s Disease
Rango, M., & Bresolin, N. (2018) · Genes · doi:10.3390/genes9050250 · Cited by 87
Patki, G., & Lau, Y. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.06.026 · Cited by 81
Ross, J. M. (2011) · Journal of Visualized Experiments · doi:10.3791/3266 · Cited by 81
Dopamine heteroreceptor complexes as therapeutic targets in Parkinson’s disease
Fuxé, K., Guidolin, D., Agnati, L. F., & Borroto‐Escuela, D. O. (2014) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.981529 · Cited by 82
“2 Effects of the A2AR antagonist MSX-3 in the Mito-Park model in mice MitoPark mice represent a genetic model with a progressive degeneration of the nigral dopamine nerve cells [116].”
BackgroundLoss of dopamine disrupts circadian rhythms in a mouse model of Parkinson's disease
Fifel, K., & Cooper, H. M. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.024 · Cited by 80
“We aimed to assess the role of DA in the circadian regulation of rest/ activity rhythms using a recently developed transgenicMitoParkmouse model of PD based on specific deletion of the gene encoding for the mitochondrial transcription factor A (Tfam) in DA neurons using the Cre–LoxP system (Ekstrand et al., 2007).”
BackgroundMethodInfluentialKienhöfer, J., Haeussler, D. J., Ruckelshausen, F., Muessig, E., Weber, K., Pimentel, D. R., Ullrich, V., Bürkle, A., & Bachschmid, M. M. (2009) · The FASEB Journal · doi:10.1096/fj.08-113571 · Cited by 79
Calcium, Bioenergetics, and Parkinson’s Disease
Zampese, E., & Surmeier, D. J. (2020) · Cells · doi:10.3390/cells9092045 · Cited by 79
Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease
Laguna, A., Schintu, N., Nobre, A., Alvarsson, A., Volakakis, N., Jacobsen, J. K., Gómez‐Galán, M., Sopova, E., Joodmardi, E., Yoshitake, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4004 · Cited by 80
Generation of Ferric Iron Links Oxidative Stress to α-Synuclein Oligomer Formation
Levin, J., Högen, T., Hillmer, A. S., Bader, B., Schmidt, F., Kamp, F., Kretzschmar, H. A., Bötzel, K., & Giese, A. (2011) · Journal of Parkinson s Disease · doi:10.3233/jpd-2011-11040 · Cited by 80
Parkinson’s disease mouse models in translational research
Antony, P. M. A., Diederich, N. J., & Balling, R. (2011) · Mammalian Genome · doi:10.1007/s00335-011-9330-x · Cited by 84
“These mice exhibit an adult-onset progressive loss of nigrostriatal dopaminergic neurons, accompanied by the formation of intraneuronal inclusions (Ekstrand and Galter 2009; Ekstrand et al. 2007).”
BackgroundMaternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice
Lippert, R. N., Hess, S., Klemm, P., Burgeno, L. M., Jahans-Price, T., Walton, M. E., Kloppenburg, P., & Brüning, J. C. (2020) · Journal of Clinical Investigation · doi:10.1172/jci134412 · Cited by 83
“WT C57BL6/N (Charles River Labs) female mice as well as Rosa26-LSL-hM3DGq (68) or Rosa26-LSL-TdTomato (Jackson Laboratory, strain 007905) female mice maintained on a C57BL6/N background were placed on a control diet containing 13% calories from fat, D12450-(B) mod (ssniff Diet), at 4 weeks of age for 7 weeks, after wh…”
BackgroundMitochondrial genome changes and neurodegenerative diseases
Pinto, M., & Moraes, C. T. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.11.012 · Cited by 75
Sterky, F. H., Hoffman, A. F., Milenkovic, D., Bao, B., Paganelli, A., Edgar, D., Wibom, R., Lupica, C. R., Olson, L., & Larsson, N. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr537 · Cited by 77
“DAT-cre (22) and Ndufs4 (18) mice were backcrossed ≥10 generations to C57Bl/6.”
BackgroundInfluentialSelf-citationAbdin, A. A., & Hamouda, H. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.08.033 · Cited by 77
“The mechanism by which inhibition of complex I lead to degeneration of dopaminergic neurons, involves activation of mitochondria-dependent apoptotic molecular pathways (Waldmeier and Tatton, 2004; Ekstrand et al., 2007).”
Αlpha-Synuclein as a Mediator in the Interplay between Aging and Parkinson’s Disease
Bobela, W., Aebischer, P., & Schneider, B. L. (2015) · Biomolecules · doi:10.3390/biom5042675 · Cited by 75
“Additionally, the progression of motor impairment clearly correlates with the loss of the TH marker, both in the striatum and in the SNpc, with the VTA being less affected [158].”
BackgroundInfluentialProspects of Neurotrophic Factors for Parkinson's Disease: Comparison of Protein and Gene Therapy
Domanskyi, A., Saarma, M., & Airavaara, M. (2015) · Human Gene Therapy · doi:10.1089/hum.2015.065 · Cited by 76
“23,24 A similar phenomenon has also been observed in genetic models of PD. 25–28 Although most of the genetic animal models of PD based on GWASs 29 show none or only mild deficits in dopamine phenotypic markers, the study by Wade-Martins and colleagues demonstrated that transgenic mice carrying the…”
Kapnick, S. M., Pacheco, S. E., & McGuire, P. J. (2017) · Metabolism · doi:10.1016/j.metabol.2017.11.010 · Cited by 76
SIRT3 Overexpression Inhibits Growth of Kidney Tumor Cells and Enhances Mitochondrial Biogenesis
Liu, H., Li, S., Liu, X., Chen, Y., & Deng, H. (2018) · Journal of Proteome Research · doi:10.1021/acs.jproteome.8b00260 · Cited by 78
Animal models for preclinical Parkinson's research: An update and critical appraisal
Cenci, M. A., & Björklund, A. (2020) · Progress in brain research · doi:10.1016/bs.pbr.2020.02.003 · Cited by 74
Mutational screening of the mortalin gene (HSPA9) in Parkinson’s disease
de Mena, L., Coto, E., Sánchez-Ferrero, E., Ribacoba, R., Guisasola, L. M., Salvador, C., Estrada, M. B., & Álvarez, V. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0273-2 · Cited by 75
Chu, Y., Goldman, J. G., Kelly, L. P., He, Y., Waliczek, T., & Kordower, J. H. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.003 · Cited by 71
“On the other hand, impaired mitochondrial function was shown to induce increased α-syn expression and formation of α-syn inclusions (Ekstrand et al., 2007; Esteves et al., 2009; Lee et al., 2002).”
BackgroundPerier, C., Bender, A., García‐Arumí, E., Melia, M., Bové, J., Laub, C., Klopstock, T., Elstner, M., Mounsey, R. B., Teismann, P., et al. (2013) · Brain · doi:10.1093/brain/awt196 · Cited by 75
“…by a conditional disruption in dopaminergic neurons of mitochondrial transcription factor A (TFAM), which regulates mitochondrial DNA transcription (Ekstrand et al., 2007), or by expression of a mitochondria-targeted restriction enzyme (PstI), which induces double-strand breaks in mitochondrial…”
BackgroundThe hidden side of Parkinson’s disease: Studying pain, anxiety and depression in animal models
Faivre, F., Joshi, A., Bézard, E., & Barrot, M. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.10.004 · Cited by 73
Wang, K. Z. Q., Zhu, J., Dagda, R. K., Uechi, G. T., Cherra, S. J., Gusdon, A. M., Balasubramani, M., & Chu, C. T. (2014) · Mitochondrion · doi:10.1016/j.mito.2014.04.008 · Cited by 73
“, 2012), most tissues in conditional TFAM knockout mice exhibit detrimental phenotypes accompanied by impaired mitochondrial function (Ekstrand et al., 2007; Li et al., 2000; Silva et al., 2000).”
BackgroundZhang, J., Culp, M. L., Craver, J., & Darley-Usmar, V. M. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14308 · Cited by 74
A Neuro-hormonal Circuit for Paternal Behavior Controlled by a Hypothalamic Network Oscillation
Stagkourakis, S., Smiley, K. O., Williams, P., Kakadellis, S., Ziegler, K., Bakker, J., Brown, R. S. E., Harkany, T., Grattan, D. R., & Broberger, C. (2020) · Cell · doi:10.1016/j.cell.2020.07.007 · Cited by 81
Dorst, M. C., Tokarska, A., Zhou, M., Lee, K., Stagkourakis, S., Broberger, C., Masmanidis, S. C., & Silberberg, G. (2020) · Nature Communications · doi:10.1038/s41467-020-18882-y · Cited by 68
Michel, P. P., Toulorge, D., Guerreiro, S., & Hirsch, É. C. (2013) · The FASEB Journal · doi:10.1096/fj.12-220418 · Cited by 70
“Another model of PD that links the death of DA neurons to activity-dependent mechanisms is the Mitopark mouse, in which the nuclear genome-encoded mitochondrial gene Tfam can be conditionally deleted in DA neurons (30).”
BackgroundBranch, S. Y., Chen, C., Sharma, R., Lechleiter, J. D., Li, S., & Beckstead, M. J. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1395-15.2016 · Cited by 69
“…age-dependent loss of nigrostriatal dopaminergic neurons, motor impairments, response to L-DOPA treatment that worsens with time, development of inclusion bodies, decreased monoamine levels in the striatum, and mild cognitive impairment (Ekstrand et al., 2007; Galter et al., 2010; Li et al., 2013).”
BackgroundInfluentialCameron, R. B., Beeson, C., & Schnellmann, R. G. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00669 · Cited by 77
Alternative oxidase rescues mitochondria-mediated dopaminergic cell loss in Drosophila
Humphrey, D. M., Parsons, R. B., Ludlow, Z. N., Riemensperger, T. D., Esposito, G., Verstreken, P., Jacobs, H. T., Birman, S., & Hirth, F. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds096 · Cited by 75
“For example, knockout of mitochondrial transcription factor TFAM in mice abolishes mtDNA expression, causing a severe respiratory chain deficiency which is embryonic lethal (12), and can result in progressive parkinsonism when targeted to dopaminergic neurons (13).”
BackgroundSex Differences in Parkinson’s Disease: From Bench to Bedside
Russillo, M. C., Andreozzi, V., Erro, R., Picillo, M., Amboni, M., Cuoco, S., Barone, P., & Pellecchia, M. T. (2022) · Brain Sciences · doi:10.3390/brainsci12070917 · Cited by 79
“The MitoPark (MP) mouse, a transgenic mitochondrial impairment model, recapitulates key features of human PD with loss of substantia nigra neurons, depletion of DA in the striatum, loss of voluntary movements, tremor, responsiveness to L-DOPA treatment, so this model spontaneously exhibits progressive motor deficits a…”
BackgroundGenetically engineered mouse models of Parkinson's disease
Crabtree, D., & Zhang, J. (2011) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2011.07.019 · Cited by 73
“MitoPark mice developed an adult-onset, slow-progressing, Parkinsonian phenotype which included motor impairment, intraneuronal inclusions, and SN cell death [109].”
BackgroundThe multi‐faceted role of mitochondria in the pathology of Parkinson’s disease
Trinh, D., Israwi, A. R., Arathoon, L. R., Gleave, J. A., & Nash, J. E. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15154 · Cited by 74
“Mutations in TFAM also cause deficits in motor function, cellular inclusions and loss of dopaminergic neurons (Ekstrand et al., 2007).”
BackgroundLiang, Z., Currais, A. J. M., Soriano‐Castell, D., Schubert, D. A., & Maher, P. A. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107749 · Cited by 71
Pandya, J. D., Grondin, R., Yonutas, H. M., Haghnazar, H., Gash, D. M., Zhang, Z., & Sullivan, P. G. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.01.018 · Cited by 70
“They may predispose the aged population to mitochondrial bioenergetics impairments and behavioral motor deficits as we have observedwith aging and could progressively lead to neurodegenerative disease states like PD (Bender et al., 2006; Ekstrand et al., 2007).”
PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction
Zhou, W., Ma, D., Sun, A. X., Tran, H.-D., Ma, D., Singh, B. K., Zhou, J., Zhang, J., Wang, D., Zhao, Y., et al. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy413 · Cited by 72
“Loss of TFAM caused early-onset Parkinsonism and aging phenotype in mice (55).”
BackgroundMitochondrial retrograde signaling regulates neuronal function
Cagin, U., Duncan, O. F., Gatt, A. P., Dionne, M., Sweeney, S. T., & Bateman, J. E. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505036112 · Cited by 66
Genetic control of midbrain dopaminergic neuron development
Blaess, S., & Ang, S. (2015) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.169 · Cited by 69
Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy
Ignatenko, O., Chilov, D., Paetau, I., de Miguel, E., Jackson, C. B., Capin, G., Paetau, A., Terzioglu, M., Euro, L., & Suomalainen, A. (2018) · Nature Communications · doi:10.1038/s41467-017-01859-9 · Cited by 66
Self-citationLi, X., Redus, L., Chen, C., Martinez, P. A., Strong, R., Li, S., & O’Connor, J. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071341 · Cited by 67
“However, cognitive impairment in PD is not particularly responsive to L-DOPA treatment [21].”
BackgroundInfluentialHeterogeneity of nervous system mitochondria: Location, location, location!
Dubinsky, J. M. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.05.020 · Cited by 67
Neuroprotection by Radical Avoidance: Search for Suitable Agents
Hardeland, R. (2009) · Molecules · doi:10.3390/molecules14125054 · Cited by 65
“Nevertheless, there is a general agreement about an age-related decay of mitochondrial functions, which is additionally aggravated in neurodegenerative disorders [7,9,11,20,54,84–86,106,108–110].”
Background
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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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.
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