Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons
Open accessAbstract
Mitochondrial dysfunction is implicated in the pathophysiology of Parkinson′s disease (PD), a common age-associated neurodegenerative disease characterized by intraneuronal inclusions (Lewy bodies) and progressive degeneration of the nigrostriatal dopamine (DA) system. It has recently been demonstrated that midbrain DA neurons of PD patients and elderly humans contain high levels of somatic mtDNA mutations, which may impair respiratory chain function. However, clinical studies have not established whether the respiratory chain deficiency is a primary abnormality leading to inclusion formation and DA neuron death, or whether generalized metabolic abnormalities within the degenerating DA neurons cause secondary damage to mitochondria. We have used a reverse genetic approach to investigate this question and created conditional knockout mice (termed MitoPark mice), with disruption of the gene for mitochondrial transcription factor A ( Tfam ) in DA neurons. The knockout mice have reduced mtDNA expression and respiratory chain deficiency in midbrain DA neurons, which, in turn, leads to a parkinsonism phenotype with adult onset of slowly progressive impairment of motor function accompanied by formation of intraneuronal inclusions and dopamine nerve cell death. Confocal and electron microscopy show that the inclusions contain both mitochondrial protein and membrane components. These experiments demonstrate that respiratory chain dysfunction in DA neurons may be of pathophysiological importance in PD.
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Written from the paper’s full text.
TL;DR
MitoPark mice with conditional Tfam disruption in midbrain dopamine neurons develop respiratory chain deficiency, adult-onset progressive parkinsonism, intraneuronal inclusions, and dopamine neuron death. The findings provide genetic evidence that respiratory chain dysfunction in dopamine neurons may be pathophysiologically important in Parkinson’s disease.
Key findings
- MitoPark mice had reduced mtDNA expression in midbrain DA neurons at 6 weeks and marked reduction of COX enzyme activity at 20 weeks.
- Motor impairment began at ≈14–15 weeks, progressed to tremor, twitching, and apparent limb rigidity at ≈20 weeks, and mice were killed at ≈45 weeks; L-DOPA improved motor performance, with older mice showing abrupt termination resembling “wearing off.”
- DA innervation loss first appeared in dorsolateral striatum at 12 weeks; TH+ midbrain neuron loss was earlier and more marked in SN than VTA, and 20-week-old MitoPark mice had DA loss plus increased HVA/DA and DOPAC/DA ratios.
- Most midbrain DA neurons contained small cytoplasmic inclusions at 6 weeks before DA cell loss; inclusions contained mitochondrial protein and membrane components by confocal and electron microscopy, but did not contain α-synuclein and persisted in α-synuclein knockout MitoPark mice.
Methods
- Reverse genetic conditional knockout: DAT-cre mice were crossed with TfamloxP/TfamloxP mice to disrupt Tfam in midbrain DA neurons; cre expression was validated by in situ hybridization and reporter mice.
- Behavioral testing used automated activity cages for locomotion and rearing, with L-DOPA plus benserazide or PBS injections; histology, immunohistochemistry, in situ hybridization, electron microscopy, confocal microscopy, and HPLC catecholamine measurements were used.
- Sample sizes included 7 MitoPark/control pairs for in situ hybridization and enzyme histochemistry, 20 pairs for immunohistochemistry, 18 mice (9 littermate pairs) for TH cell counts, and 9 animals for aggregate counts and size measurements.
Limitations
- The paper states that the mechanism whereby respiratory chain deficiency leads to inclusion formation needs to be elucidated, that there was no evidence of α-synuclein in the inclusions, and that there is no absolute link between respiratory chain dysfunction and oxidative stress.
- The text makes evident that this is a mouse model rather than human PD, that the inclusions differ from human Lewy bodies in α-synuclein content, and that the h116–131 antibody reacted with an unknown inclusion component.
- The paper does not include a formal limitations section; additional limitations evident from the text include reliance on a single conditional knockout model and unresolved specificity of one α-synuclein antibody.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 19 cited sources checked · 0 supported · 0 flagged
- Findingown data§ Results
MitoPark mice have reduced mtDNA expression in midbrain DA neurons.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
MitoPark mice show dopamine nerve cell death.
“accompanied by formation of intraneuronal inclusions and dopamine nerve cell death.”
Quote in the paperSubstantial claim - Findingown data§ Results
MitoPark mice have respiratory chain deficiency in midbrain DA neurons.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Results
MitoPark mice show no increased embryonic or neonatal lethality.
“There was no increased embryonic or neonatal lethality in MitoPark mice.”
Quote in the paperNot a substantial claim - Findingown data§ Results
Five additional α-synuclein antibodies were not immunoreactive with the inclusions in MitoPark mice.
“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.”
Quote in the paperSubstantial claim
- Findingown data§ Abstract
MitoPark mice form intraneuronal inclusions.
“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).”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data§ Results
In MitoPark mice, the nucleus-encoded α-subunit of mitochondrial ATP synthase partially overlaps with, is juxtaposed to, or surrounds the intraneuronal inclusions.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Results
MitoPark mice first show decreased locomotion and reduced exploratory behavior at age ≈14-15 weeks.
“Decreased locomotion and reduced exploratory behavior first became apparent at age ≈14–15 weeks.”
Quote in the paperSubstantial claim - Findingown data§ Results
Absence of a functional α-synuclein gene has no obvious impact on the phenotype in MitoPark mice.
“The absence of a functional α-synuclein gene had no obvious impact on the phenotype in MitoPark mice (data not shown).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
The intraneuronal inclusions in MitoPark mice contain both mitochondrial protein and membrane components.
“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).”
Quote in the paperSubstantial claim - Also stated in: § Results · hedged
- Findingown data§ Results
MitoPark mice show progressive decline of locomotion and rearing from age 14 weeks.
“We performed behavioral tests to obtain quantitative measurements of the clinically obvious motor impairment in MitoPark mice and found progressive decline of both locomotion (Fig. 2A–C) and rearing (Fig. 2D) in MitoPark mice from the age of 14 weeks.”
Quote in the paperSubstantial claim - Findingown data§ Results
A majority of midbrain DA neurons in 6-week-old MitoPark mice contain small cytoplasmic aggregates.
“However, the DA neurons did not appear normal at this clinically presymptomatic stage, as a majority of them contained small cytoplasmic aggregates (Fig. 4A–D).”
Quote in the paperSubstantial claim - Findingown data§ Results
Electron microscopy of MitoPark mice at 11 weeks shows large, clearly delineated, partially electron-dense bodies often located in dendritic structures close to neuronal somata.
“Ultrathin sections from the midbrain of MitoPark and control mice at age 11 weeks were examined by electron microscopy. In MitoPark mice only, we observed large, clearly delineated and partially electron-dense bodies often located in dendritic structures close to neuronal somata (Fig. 5).”
Quote in the paperSubstantial claim - Findingown data§ Results
An identical L-DOPA dose elicited a more pronounced and longer lasting locomotion response in younger compared with older MitoPark mice.
“an identical L-DOPA dose elicited a more pronounced and longer lasting locomotion response in younger in comparison with older MitoPark mice (Fig. 2 E and F).”
Quote in the paperSubstantial claim - Findingown data§ Results
MitoPark mice had to be killed at ≈45 weeks of age because of poor general condition.
“and MitoPark mice had to be killed at ≈45 weeks of age because of poor general condition.”
Quote in the paperNot a substantial claim - Findingown data§ Results
The h116-131 α-synuclein antibody is strongly immunoreactive with intraneuronal inclusions in MitoPark mice.
“A polyclonal antibody raised against a peptide of human α-synuclein (h116–131), was strongly immunoreactive with the intraneuronal inclusions.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
MitoPark mice develop adult-onset, slowly progressive impairment of motor function.
“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.”
- Also stated in: § Results · plain
“Decreased locomotion and reduced exploratory behavior first became apparent at age ≈14–15 weeks.”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data§ Results
DA nerve cell loss in 20-week-old MitoPark mice results in corresponding loss of DA in different parts of the nigrostriatal system.
“We performed neurochemical studies, which confirmed that the DA nerve cell loss resulted in a corresponding loss of DA in different parts of the nigrostriatal system of 20-week-old MitoPark mice (Fig. 3 J and K).”
Quote in the paperSubstantial claim - Findingown data§ Results
Inclusions were not found in non-DA neurons in MitoPark mice.
“Inclusions were not found in non-DA neurons.”
Quote in the paperNot a substantial claim - Interpretationown data§ Abstract
Respiratory chain dysfunction in DA neurons may be of pathophysiological importance in PD.
“These experiments demonstrate that respiratory chain dysfunction in DA neurons may be of pathophysiological importance in PD.”
- Also stated in: § Abstract · hedged
“Our findings thus provide experimental support for the hypothesis that acquired respiratory chain dysfunction may be of pathophysiological importance in PD.”
Quote in the paperSubstantial claim- Rests on an assumption: 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.
- Also stated in: § Abstract · hedged
- Premisecitation§ Abstract
Mitochondrial dysfunction is implicated in the pathophysiology of Parkinson's disease.
“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.”
- Also stated in: § Abstract · hedged
“mitochondrial dysfunction has also been implicated in common forms of age-associated neurodegenerative diseases (2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Dauer W, Przedborski S. Neuron. 2003;39:889–909. doi: 10.1016/s0896-6273(03)00568-3. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Also stated in: § Abstract · hedged
- Interpretationown data§ Results
Dysfunctional mitochondria have a direct role in the formation of intracytoplasmic inclusions in MitoPark mice.
“These data strongly suggest that dysfunctional mitochondria have a direct role in the formation of the intracytoplasmic inclusions.”
- Also stated in: § Discussion · boosted
“We present evidence that dysfunctional mitochondria directly participate in inclusion formation.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Interpretationown data§ Results
Reduced mtDNA expression causes respiratory chain deficiency in midbrain DA neurons of MitoPark mice.
“These findings show that there is a severe reduction of mtDNA expression, which, in turn, causes a severe respiratory chain deficiency in midbrain DA neurons of MitoPark mice.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
A possible mitochondrial etiology for PD does not automatically mean that reactive oxygen species and oxidative stress are of major importance.
“It should therefore be emphasized that a possible mitochondrial etiology for PD does not automatically mean that reactive oxygen species and oxidative stress are of major importance.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
In a mouse model with progressive cardiomyopathy induced by tissue-specific Tfam knockout causing mtDNA depletion, gene expression studies demonstrated strong induction of LON-protease expression.
“Gene expression studies in a mouse model with progressive cardiomyopathy, induced by tissue-specific Tfam knockout causing mtDNA depletion, has demonstrated a strong induction of LON-protease expression (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Hansson A, Hance N, Dufour E, Rantanen A, Hultenby K, Clayton DA, Wibom R, Larsson NG. Proc Natl Acad Sci USA. 2004;101:3136–3141. doi: 10.1073/pnas.0308710100. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Discussion
Mouse models with decreased mtDNA expression have increased cell death with little or no increase of oxidative stress.
“We have studied a variety of mouse models with decreased mtDNA expression (10, 12–18) and such mice have increased cell death with little or no increase of oxidative stress (18, 30).”
Quote in the paperSubstantial claim0 of 9 sources checked- cites [10] Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly Y-M, Gidlöf S, Oldfors A, Wibom R, et al. Nature. 2004;429:417–423. doi: 10.1038/nature02517. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
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Not checked in the free run.
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Not checked in the free run.
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Not checked in the free run.
- Interpretationown data§ Discussion
Reduced mtDNA expression may be an etiological event in PD.
“In addition, our results provide experimental support for the hypothesis that reduced mtDNA expression may be an etiological event in PD.”
Quote in the paperSubstantial claim- Rests on an assumption: 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.
- Interpretationreasoning§ Discussion
MitoPark mice may provide a platform to study key pathophysiological events in PD.
“and the MitoPark mice may therefore provide a platform to study key pathophysiological events in PD.”
Quote in the paperSubstantial claim - Interpretationcitation§ Discussion
There is no absolute link between respiratory chain dysfunction and oxidative stress.
“However, there is no absolute link between respiratory chain dysfunction and oxidative stress.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
Reduced mtDNA expression leads to an excess of nucleus-encoded respiratory chain subunits that must be degraded by the mitochondrial proteolytic system.
“Reduced mtDNA expression leads to an excess of nucleus-encoded respiratory chain subunits that must be degraded by the mitochondrial proteolytic system.”
Quote in the paperSubstantial claim
- May combine two claims. 13
- Classified as probably not a substantial claim. 6
May combine two claims.
Findingown data§ ResultsIn MitoPark mice lacking a functional α-synuclein gene, inclusions remain and are immunoreactive with the h116-131 antibody.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsMitoPark mice show slow progressive loss of TH-expressing midbrain neurons, with more marked and earlier onset in SN than VTA.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsLoss of DA innervation in MitoPark mice first appears in dorsolateral striatum at age 12 weeks and progresses to involve most of the dorsal and ventral striatum with age.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsInclusions are present in most midbrain DA neurons of MitoPark mice and their mean size increases as neurodegeneration progresses.
“The inclusions were present in most midbrain DA neurons (Fig. 4C) and their mean size increased as neurodegeneration progressed (Fig. 4D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsSome inclusion bodies in MitoPark mice have amorphous content and a diffuse lining, whereas others display tubular formations and are surrounded by distinct double layer membranes.
“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).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ ResultsAt 6 weeks, MitoPark mice show no observable DA cell loss despite severely reduced mtDNA expression in midbrain DA neurons.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ Resultsα-synuclein is not needed for the PD phenotype or for development of DA neuron inclusions in MitoPark mice.
“Thus α-synuclein was neither needed for the PD phenotype nor the development of DA neuron inclusions in our mice.”
Quote in the paperSubstantial claim- Rests on an assumption: α-synuclein is commonly found in Lewy bodies in human PD.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DiscussionLewy bodies can have a variety of morphological shapes and their morphology may evolve with time.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Shults CW. Proc Natl Acad Sci USA. 2006;103:1661–1668. doi: 10.1073/pnas.0509567103. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone given§ DiscussionThe morphology of Lewy bodies has mainly been studied in brain tissue from end-stage PD patients, and it is not well established how these aggregates appear at early disease stages.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown data§ ResultsDAT-cre mice express cre mRNA and enzymatically active cre-recombinase protein in DA neurons of the midbrain.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Soriano P. Nat Genet. 1999;21:70–71. doi: 10.1038/5007. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone given§ ResultsThe differential degeneration (earlier and more marked in SN than VTA) is also characteristic of PD in man.
“This differential degeneration is also characteristic of PD in man.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ AbstractMidbrain DA neurons of PD patients and elderly humans contain high levels of somatic mtDNA mutations, which may impair respiratory chain function.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
- Also stated in: § Abstract · boosted
May combine two claims.
Interpretationown data§ DiscussionRespiratory chain deficiency in DA neurons in mice leads to slowly progressive neuronal degeneration, behavioral disturbances, and intraneuronal inclusions characteristic of parkinsonism.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DiscussionIn vitro studies have shown that α-synuclein can interact directly with lipids in membranes and with proteins of the mitochondrial respiratory chain.
“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).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [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]
Not checked in the free run.
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Not checked in the free run.
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Not checked in the free run.
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Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown data§ Materials and MethodsDA neuron counts were performed on coded slides.
“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).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisecitation§ DiscussionThe mitochondrial network has an elaborate system for protein degradation involving membrane-bound AAA-proteases and LON protease in the matrix.
“The mitochondrial network has an elaborate system for protein degradation involving membrane bound AAA-proteases and LON protease in the matrix (31).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Rugarli EI, Langer T. Trends Mol Med. 2006;12:262–269. doi: 10.1016/j.molmed.2006.04.002. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
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?
For all targeted cell types, TFAM depletion leads to mtDNA depletion, mitochondrial transcript depletion and respiratory chain deficiency, except not reported for midbrain DA neurons.
“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
TFAM deletion in mouse pyramidal neurons causes mitochondrial late-onset neurodegeneration (MILON), whereas deletion in mouse midbrain DA neurons leads to PD.
“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
Manipulating nuclear genes regulating mtDNA maintenance and replication (TFAM, POLG, PEO1) is a more successful approach to developing mouse models of mitochondrial disease.
“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]
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Self-citationSomatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production
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Self-citationMitochondrial DNA mutations in human colonic crypt stem cells
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The MPTP model of Parkinson's disease
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Self-citationMitochondrial Lipid Abnormality and Electron Transport Chain Impairment in Mice Lacking α-Synuclein
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Self-citationRole of Cytochrome c as a Stimulator of α-Synuclein Aggregation in Lewy Body Disease
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Self-citationCytochrome c oxidase deficient cells accumulate in the hippocampus and choroid plexus with age
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The transcription machinery in mammalian mitochondria
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Self-citationMutant and Wild-Type α-Synuclein Interact with Mitochondrial Cytochrome C Oxidase
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Time-course of trimethyltin effects on the monoaminergic systems of the rat brain.
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Self-citation
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PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
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Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice
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Genetic Animal Models of Parkinson's Disease
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“…of PD, including age-dependent selective DA neuron loss, Lewy body-like filamentous inclusions containing a-synuclein, and DA-responsive locomotor deficits (Feany and Bender, 2000), although whether there is actual loss of DA neurons or just loss of DA markers is not clear (Pesah et al., 2005).”
Mitochondrial Dysfunction in Neurodegenerative Diseases
Johri, A., & Beal, M. F. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.192138 · Cited by 806 · see citing works
“The MitoPark mice survive to adulthood and then slowly develop a Parkinsonian phenotype (Ekstrand et al., 2007; Galter et al., 2010).”
BackgroundNarendra, D. P., Kane, L. A., Hauser, D. N., Fearnley, I. M., & Youle, R. J. (2010) · Autophagy · doi:10.4161/auto.6.8.13426 · Cited by 789 · see citing works
“The pathophysiological significance of mitochondrial aggregation is less clear, but interestingly in MitoPark mice, a model of progressive parkinsonism, damaged mitochondria are sequestered in intracellular inclusions that bear some resemblance to Lewy bodies (although they lack alpha-synuclein, a key component of Lew…”
BackgroundHuman mitochondrial DNA: roles of inherited and somatic mutations
Schon, E. A., DiMauro, S., & Hirano, M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3275 · Cited by 757 · see citing works
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Mitochondrial dysfunction in Parkinson's disease
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“A conditional knockout of TFAM in midbrain dopaminergic neurons caused reduced mtDNA expression, respiratory chain deficiency and neuronal cell death, leading to progressive, L-dopa-responsive impairment of motor functions [98].”
BackgroundMitochondrial DNA mutations and human disease
Tuppen, H. A. L., Blakely, E. L., Turnbull, D. M., & Taylor, R. W. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.09.005 · Cited by 676 · see citing works
“TFAM [176–182], POLG (‘Mutator’ model) [183], and PEO1 (Twinkle; ‘Deletor’ model) [184].”
Exner, N., Lutz, A. K., Haass, C., & Winklhofer, K. F. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.170 · Cited by 652 · see citing works
Disruption of mitochondrial complex I induces progressive parkinsonism
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Somatic Mitochondrial DNA Mutations in Mammalian Aging
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Oxidative Stress in Neurodegenerative Diseases: From a Mitochondrial Point of View
Cenini, G., Lloret, A., & Cascella, R. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/2105607 · Cited by 435 · see citing works
“In particular, in some models of PD, it has been shown that environmental xenobiotics were extremely toxic and caused mitochondrial dysfunction in dopaminergic neurons leading to parkinsonian phenotypes [144].”
BackgroundSchapira, A. H. V. (2012) · The Lancet · doi:10.1016/s0140-6736(11)61305-6 · Cited by 499 · see citing works
Parkinson’s disease: animal models and dopaminergic cell vulnerability
Blesa, J., & Przedborski, S. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00155 · Cited by 483 · see citing works
“…transcription factor A in DA neurons (MitoPark) results in a parkinsonism phenotype in mice that includes an adult-onset, slowly progressive impairment of motor function, DA neuron death, degeneration of nigrostriatal pathways and intraneuronal inclusions (Ekstrand et al., 2007; Good et al., 2011).”
BackgroundMitochondrial Diseases of the Brain
Chaturvedi, R. K., & Beal, M. F. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.03.018 · Cited by 416 · see citing works
“These mice show reduced mtDNA expression, reduced respiratory chain function in DA neurons, and a progressive PD phenotype, consistent with involvement of respiratory chain dysfunction in PD pathogenesis[75].”
BackgroundNurr1 Is Required for Maintenance of Maturing and Adult Midbrain Dopamine Neurons
Kadkhodaei, B., Ito, T., Joodmardi, E., Mattsson, B., Rouillard, C., Carta, M., Muramatsu, S.-I., Sumi-Ichinose, C., Nomura, T., Metzger, D., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3910-09.2009 · Cited by 382 · see citing works
“The generation of dopamine transporter (DAT )–Cre mutant mice has been described previously (Ekstrand et al., 2007).”
BackgroundMethodSelf-citationCalabrese, V., Santoro, A., Monti, D., Crupi, R., Di Paola, R., Latteri, S., Cuzzocrea, S., Zappia, M., Giordano, J., Calabrese, E. J., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.10.379 · Cited by 356 · see citing works
“When mitochondrial transcription factor A, which is essential for mitochondrial DNA expression, is selectively depleted in DA neurons of MitoPark mice, mitochondria in DA neurons of the substantia nigra develop a defective electron transport chain, leading to neuronal degeneration in adulthood [39].”
BackgroundJin, H., Kanthasamy, A., Ghosh, A., Anantharam, V., Kalyanaraman, B., & Kanthasamy, A. G. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.007 · Cited by 362 · see citing works
“These mice exhibit reduced mtDNA expression, attenuated expression of respiratory chain function in dopaminergic neurons in nigra along with behavioral impairments and striatal dopamine depletion, mimicking progressive PD phenotypes starting from 18 weeks of age [89].”
BackgroundCervo, P. R. D. V., Romanov, R. A., Spigolon, G., Masini, D., Martín‐Montañez, E., Toledo, E. M., Manno, G. L., Feyder, M. T., Pifl, C., Ng, Y. H., et al. (2017) · Nature Biotechnology · doi:10.1038/nbt.3835 · Cited by 357 · see citing works
Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation
Norat, P., Soldozy, S., Sokolowski, J. D., Gorick, C. M., Kumar, J. S., Chae, Y., Yağmurlu, K., Prada, F. U., Walker, M., Levitt, M. R., et al. (2020) · npj Regenerative Medicine · doi:10.1038/s41536-020-00107-x · Cited by 353 · see citing works
“To further address this question, Ekstrand et al.34 conditionally deleted the gene encoding mitochondrial transcription factor A (Tfam) in dopaminergic neurons.”
BackgroundDamage to dopaminergic neurons by oxidative stress in Parkinson's disease (Review)
Guo, J., Zhao, X., Li, Y., Li, G., & Liu, X. (2018) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2018.3406 · Cited by 347 · see citing works
“Inhibition of mtDNA expression leads to dysfunction in the respiratory chain in dopaminergic neurons accompanied by progressive parkinsonism in mouse models (59).”
BackgroundDopamine Is Required for the Neural Representation and Control of Movement Vigor
Panigrahi, B., Martin, K. A., Li, Y., Graves, A. R., Vollmer, A., Olson, L., Mensh, B. D., Karpova, A. Y., & Dudman, J. T. (2015) · Cell · doi:10.1016/j.cell.2015.08.014 · Cited by 315 · see citing works
Self-citationImpaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease
Büeler, H. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.03.006 · Cited by 326 · see citing works
The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms
Kang, I., Chu, C. T., & Kaufman, B. A. (2018) · FEBS Letters · doi:10.1002/1873-3468.12989 · Cited by 325 · see citing works
Mitochondrial DNA mutations in disease and aging
Park, C. B., & Larsson, N. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201010024 · Cited by 326 · see citing works
“, 2001), dopamine neurons (Ekstrand et al., 2007), and pancreatic cells (Silva et al.”
BackgroundSelf-citationFell, M. J., Mirescu, C., Basu, K., Cheewatrakoolpong, B., DeMong, D. E., Ellis, J. M., Hyde, L. A., Lin, Y., Markgraf, C. G., Mei, H., et al. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.115.227587 · Cited by 310 · see citing works
“In addition to exploring the role of LRRK2 kinase activity in lung, we also evaluated the disease-modifying potential of MLi-2 in the MitoPark mouse model of PD (Ekstrand et al., 2007).”
BackgroundMethodInfluentialMitochondrial Biology and Parkinson's DiseasePreprint
Perier, C., & Vila, M. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009332 · Cited by 304 · see citing works
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“Consistent with findings in other TFAM-deficient tissues (36, 39, 40, 42), RPE Δ MT RPE cells develop enlarged mitochondria with tubular cristae (Figure 1K), which can occupy as much as 70% of the cellular area in cross section (Figure 1L).”
Beckervordersandforth, R., Ebert, B., Schäffner, I., Moss, J., Fiebig, C., Shin, J., Moore, D. L., Ghosh, L., Trinchero, M. F., Stockburger, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2016.12.017 · Cited by 303 · see citing works
“A number of studies have found that Tfam conditional knockout mice almost invariably develop a phenotype only after weeks to months following disruption of the Tfam locus, most likely owing to the long half-life of Tfam transcripts, Tfam protein, and Tfam targets (Ekstrand et al., 2007; Silva et al., 2000; Sörensen et…”
BackgroundRoss, J. M., Öberg, J., Brené, S., Coppotelli, G., Terzioglu, M., Pernold, K., Goiny, M., Sitnikov, R., Kehr, J., Trifunovic, A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008189107 · Cited by 299 · see citing works
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“Neurons depend on oxidative phosphorylation for energy supply and thus are vulnerable to mitochondrial compromise in vivo (18, 19).”
BackgroundMethodInfluentialSelf-citationMitochondrial Approaches for Neuroprotection
Chaturvedi, R. K., & Beal, M. F. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1427.027 · Cited by 294 · see citing works
Mitochondrial DNA nucleoid structure
Bogenhagen, D. F. (2012) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2011.11.005 · Cited by 290 · see citing works
Understanding wiring and volume transmission
Agnati, L. F., Guidolin, D., Guescini, M., Genedani, S., & Fuxé, K. (2010) · Brain Research Reviews · doi:10.1016/j.brainresrev.2010.03.003 · Cited by 283 · see citing works
The discovery of central monoamine neurons gave volume transmission to the wired brain
Fuxé, K., Dahlström, A. B., JONSSON, G., Marcellino, D. J., Guescini, M., Dam, M., Manger, P. R., & Agnati, L. F. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.10.012 · Cited by 285 · see citing works
“tion of the gene for mitochondrial transcription factor A (Tfam) in DA neurons (Ekstrand et al., 2007).”
BackgroundCell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps
Levy, O. A., Malagelada, C., & Greene, L. A. (2009) · APOPTOSIS · doi:10.1007/s10495-008-0309-3 · Cited by 287 · see citing works
Lau, Y.-S., Patki, G., Das-Panja, K., Le, W.-D., & Ahmad, S. O. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07626.x · Cited by 275 · see citing works
“Parkinsonian symptoms are replicated in genetically engineered mice that are deficient in mitochondrial respiratory chains (Ekstrand et al., 2007).”
BackgroundMitochondrial dysfunction in the limelight of Parkinson's disease pathogenesis
Banerjee, R., Starkov, A. A., Beal, M. F., & Thomas, B. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.11.007 · Cited by 256 · see citing works
“Interestingly ablation of TFAM in nigrostriatal dopaminergic neurons of mice is known to cause progressive loss of SNpc dopaminergic neurons and L-DOPA responsive motor deficits due to reduced mtDNA expression and respiratory chain deficiency [103].”
BackgroundThe role of the LRRK2 gene in Parkinsonism
Li, J.-Q., Tan, L., & Yu, J.-T. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-47 · Cited by 249 · see citing works
“There are more compelling evidences which come from mice possessing conditional knockout of mitochondrial transcription factor A in DA neurons, showing reduced mtDNA expression which in turn leads to a parkinsonism phenotype characterized by adult onset of a progressive impairment of motor function accompanied by form…”
BackgroundUittenbogaard, M. N., & Chiaramello, A. (2014) · Current Pharmaceutical Design · doi:10.2174/1381612820666140305224906 · Cited by 240 · see citing works
Calcium, Bioenergetics, and Neuronal Vulnerability in Parkinson's Disease
Surmeier, D. J., & Schumacker, P. T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.410530 · Cited by 233 · see citing works
“Like other neurons, SNc DA neurons depend on mtDNA for survival (45), so the accumulation of mutations can lead to the development of a bioenergetic deficiency that becomes lethal over time.”
BackgroundSurmeier, D. J., Guzman, J. N., Sanchez-Padilla, J., & Schumacker, P. T. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.08.045 · Cited by 236 · see citing works
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript in DA neurons in a way that mimics accumulating mtDNA mutations and produces an adult onset form of PD that is accompanied by intraneuronal inclusions and cell death (Ekstrand et al., 2007).”
BackgroundLoss of Mitochondrial Fission Depletes Axonal Mitochondria in Midbrain Dopamine Neurons
Berthet, A., Margolis, E. B., Zhang, J., Hsieh, I., Zhang, J., Hnasko, T. S., Ahmad, J., Edwards, R. H., Sesaki, H., Huang, E. J., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0930-14.2014 · Cited by 226 · see citing works
“are also less affected than those projecting to the CPu in PD and in pharmacologic and genetic models of mitochondrial dysfunction that target mitochondria (Heikkila et al., 1984; Miller et al., 1997; Betarbet et al., 2000; Ekstrand et al., 2007; Pham et al., 2012), but the properties of these surviving DA neurons hav…”
Mitochondrial DNA Depletion in Respiratory Chain–Deficient P arkinson Disease Neurons
Grünewald, A., Rygiel, K. A., Hepplewhite, P. D., Morris, C. M., Picard, M. A., & Turnbull, D. M. (2015) · Annals of Neurology · doi:10.1002/ana.24571 · Cited by 230 · see citing works
“In line with our hypothesis stating that TFAM deficiency induces mtDNA depletion in IPD, conditional silencing of TFAM provokes PD-like features such as respiratory chain dysfunction, degeneration of dopaminergic SN neurons, and progressive impairment of motor function in mice.(33,34) Remarkably, in addition to its ef…”
BackgroundTrichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity
Gash, D. M., Rutland, K., Hudson, N. L., Sullivan, P. G., Bing, G., Cass, W. A., Pandya, J. D., Liu, M., Choi, D. Y., Hunter, R. L., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21288 · Cited by 223 · see citing works
A VTA GABAergic Neural Circuit Mediates Visually Evoked Innate Defensive Responses
Zhou, Z., Liu, X., Chen, S., Zhang, Z., Liu, Y., Montardy, Q., Tang, Y., Wei, P., Liu, N., Li, L., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.05.027 · Cited by 211 · see citing works
Zinovkin, R. A., & Zamyatnin, A. A. (2019) · Current Molecular Pharmacology · doi:10.2174/1874467212666181127151059 · Cited by 209 · see citing works
The role of mitochondrial dysfunction in age-related diseases
Lane, R. K., Hilsabeck, T., & Rea, S. L. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.05.021 · Cited by 205 · see citing works
“It should be noted that while these mice have been found to have intraneuronal inclusions, the aggregates did not contain α-syn [86].”
BackgroundThe pathophysiology of mitochondrial disease as modeled in the mousePreprint
Wallace, D. C., & Fan, W. (2009) · Genes & Development · doi:10.1101/gad.1784909 · Cited by 201 · see citing works
“These results support the hypothesis that mitochondrial dysfunction results in PD and raises the possibility that damaged mitochondria nucleate Lewy body formation (Ekstrand et al. 2007).”
ResultBehavioral phenotyping of mouse models of Parkinson's disease
Taylor, T. N., Greene, J. G., & Miller, G. W. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.03.004 · Cited by 198 · see citing works
“When challenged with L-DOPA, the LRRK2, Pitx3-aphakia, MitoPark, and VMAT2-deficient mice all displayed increases in locomotor activity [31-34].”
BackgroundGegg, M. E., Cooper, J. M., Schapira, A. H. V., & Taanman, J.-W. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004756 · Cited by 198 · see citing works
“Furthermore, deleted mitochondrial DNA (mtDNA) species have been reported to accumulate in the neurons of PD substantia nigra [4], while mice with reduced mtDNA copy number in dopaminergic neurons exhibit a parkinsonian phenotype [5].”
Franco-Iborra, S., Vila, M., & Perier, C. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00342 · Cited by 194 · see citing works
“…disruption in dopaminergic neurons of mitochondrial transcription factor A (TFAM), which regulates mtDNA transcription, leads to a decrease in mtDNA content and cytochrome c oxidase enzymatic activity, which is associated with a progressive parkinsonism phenotype (Ekstrand et al., 2007).”
BackgroundMitochondrial abnormalities in temporal lobe of autistic brain
Tang, G., Gutierrez Rios, P., Kuo, S.-H., Akman, H. O., Rosoklija, G., Tanji, K., Dwork, A., Schon, E. A., DiMauro, S., Goldman, J., et al. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.01.006 · Cited by 194 · see citing works
Ay, M., Luo, J. D., Langley, M. R., Jin, H., Anantharam, V., Kanthasamy, A., & Kanthasamy, A. G. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14033 · Cited by 191 · see citing works
Neuroprotection by a mitochondria-targeted drug in a Parkinson's disease model
Ghosh, A., Chandran, K., Kalivendi, S. V., Joseph, J., Antholine, W. E., Hillard, C. J., Kanthasamy, A., Kanthasamy, A. G., & Kalyanaraman, B. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.08.028 · Cited by 191 · see citing works
“In this regard, it is important to elucidate the neuroprotective effect of MTAs such as Mito-Q in recently established genetic models of PD [63,64].”
BackgroundChen, L., Xie, Z., Turkson, S., & Zhuang, X. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0089-14.2015 · Cited by 185 · see citing works
“In the MitoPark mice, mitochondrial inclusions are essentially abnormally enlarged mitochondria (Ekstrand et al., 2007).”
BackgroundTüfekçi, K. U., Bayin, E. C., Genç, Ş., & Genç, K. (2011) · Parkinson s Disease · doi:10.4061/2011/314082 · Cited by 181 · see citing works
“When a conditional Tfam knockout mouse in midbrain dopaminergic neurons was generated, decreased mtDNA expression, respiratory chain deficiency, and neuronal cell death leading to staggered L-dopa-responsive impairment of motor functions were observed [31].”
BackgroundDeBalsi, K. L., Hoff, K. E., & Copeland, W. C. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.04.006 · Cited by 180 · see citing works
Modeling Parkinson's Disease in Primates: The MPTP ModelPreprint
Porras, G., Li, Q., & Bézard, E. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009308 · Cited by 180 · see citing works
“The pathogenic models include the MPTP toxin models (as well as the non-PD-related genetic mutations such as the MitoPark mice (Ekstrand et al. 2007).”
BackgroundLu, X., Fleming, S. M., Meurers, B. H., Ackerson, L. C., Mortazavi, F., Lo, V., Hernandez, D., Sulzer, D., Jackson, G. R., Maidment, N. T., et al. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.5351-08.2009 · Cited by 177 · see citing works
“, DA-neuron-specific deletion of Tfam) (Hwang et al., 2005; Sgadò et al., 2006; Caudle et al., 2007; Ekstrand et al., 2007; Kramer et al., 2007), but, in most cases, the loss of DA neurons in these models occurs early in development, and/or their direct relevance to PD remains hypothetical.”
BackgroundMitochondrial Biogenesis in Neurons: How and Where
Cardanho‐Ramos, C., & Morais, V. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313059 · Cited by 179 · see citing works
“This was accompanied by decreased locomotion and an increased tremor, a phenotype characteristic of PD [61].”
BackgroundParkin protects mitochondrial genome integrity and supports mitochondrial DNA repair
Rothfuss, O. C., Fischer, H., Hasegawa, T., Maisel, M., Leitner, P., Miesel, F., Sharma, M., Bornemann, A., Berg, D., Gasser, T., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp327 · Cited by 177 · see citing works
“The knockout mice showed reduced mtDNA expression and respiratory chain deficiency, which led to motor function impairment, intra-neuronal inclusions and dopaminergic cell loss (63).”
BackgroundLimitations of Animal Models of Parkinson's Disease
Potashkin, J. A., Blume, S. R., & Runkle, N. K. (2010) · Parkinson s Disease · doi:10.4061/2011/658083 · Cited by 180 · see citing works
“One of the most promising models in this category is the MitoPark mouse [36].”
BackgroundMandemakers, W. J., Morais, V. A., & Strooper, B. D. (2007) · Journal of Cell Science · doi:10.1242/jcs.03443 · Cited by 176 · see citing works
“showed that the specific inactivation of mitochondrial transcription factor A (Tfam) in dopaminergic neurons leads to defects in the OXPHOS pathway that result in PD-like symptoms in mice (Ekstrand et al., 2007).”
BackgroundHsieh, T.-H., Kuo, C.-W., Hsieh, K.-H., Shieh, M.-J., Peng, C.-W., Chen, Y.-C., Chang, Y.-L., Huang, Y.-Z., Chen, C.-C., Chang, P.-K., et al. (2020) · Brain Sciences · doi:10.3390/brainsci10040206 · Cited by 174 · see citing works
“The MitoPark PD mouse can exhibit the cardinal features of PD, such as the adult onset of degeneration in dopaminergic neurons and the progressive deterioration in motor functions [31,32].”
BackgroundInfluentialParkinson’s disease: genetic versus toxin‐induced rodent models
Terzioglu, M., & Galter, D. (2008) · FEBS Journal · doi:10.1111/j.1742-4658.2008.06302.x · Cited by 173 · see citing works
Self-citationMitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons
Lee, S., Sterky, F. H., Mourier, A., Terzioglu, M., Cullheim, S., Olson, L., & Larsson, N. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds352 · Cited by 177 · see citing works
“Mice with loxP-flanked Mfn1 or Mfn2 alleles were obtained from Taconic and crossed with DAT-cre mice (4).”
BackgroundMethodInfluentialSelf-citationDopamine: A Modulator of Circadian Rhythms in the Central Nervous System
Korshunov, K. S., Blakemore, L. J., & Trombley, P. Q. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00091 · Cited by 173 · see citing works
“, VTA and SN) dopaminergic neurons (Ekstrand et al., 2007; Galter et al., 2010; Fifel and Cooper, 2014).”
BackgroundThe Parkinson Disease Mitochondrial Hypothesis
Franco-Iborra, S., Vila, M., & Perier, C. (2015) · The Neuroscientist · doi:10.1177/1073858415574600 · Cited by 169 · see citing works
Pham, A. H., Meng, S., Chu, Q. N., & Chan, D. C. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds311 · Cited by 166 · see citing works
“In contrast, disruption of mitochondrial function by the loss of mitochondrial transcription factor A (Tfam) results in dopamine cell death that is associated with reduced mitochondrial DNA content and severe respiratory chain deficiency (45,46).”
BackgroundRieker, C., Engblom, D., Kreiner, G., Domanskyi, A., Schober, A., Stotz, S., Neumann, M., Yuan, X., Grummt, I., Schütz, G., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0590-10.2011 · Cited by 162 · see citing works
“A mutant mouse lacking the mitochondrial transcription factor A (Tfam) in dopaminergic neurons shows that dysfunction of the respiratory chain might be important in the pathogenesis of parkinsonism (Ekstrand et al., 2007).”
BackgroundA tale on animal models of Parkinson's disease
Bézard, E., & Przedborski, S. (2011) · Movement Disorders · doi:10.1002/mds.23696 · Cited by 158 · see citing works
“The Larsson group has created conditional knockout mice (termed MitoPark mice) with a disruption in the gene for mitochondrial transcription factor A (Tfam) in dopaminergic neurons.(39) The authors have reported that these knockout mice have reduced mitochondrial DNA expression and respiratory chain deficiency in midb…”
BackgroundMitochondrial Dysfunction in Parkinson's Disease
Keane, P. C., Kurzawa‐Akanbi, M., Blain, P. G., & Morris, C. M. (2011) · Parkinson s Disease · doi:10.4061/2011/716871 · Cited by 177 · see citing works
“The mitochondrial transcriptional factor A (TFAM) regulates transcription of mtDNA and was linked to PD by the finding that TFAM knockout mice (MitoPark mice) had reduced mtDNA expression and respiratory chain deficiency in SNpc DA neurons, which lead to a Parkinsonian phenotype [128].”
BackgroundEngrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults
Alvarez-Fischer, D., Fuchs, J., Castagner, F., Stettler, O., Massiani-Beaudoin, O., Moya, K. L., Bouillot, C., Oertel, W. H., Lombès, A., Faigle, W., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2916 · Cited by 150 · see citing works
“Given the importance of mitochondria and complex I activity in Parkinson's diseas”
BackgroundA Futile Battle? Protein Quality Control and the Stress of Aging
Higuchi‐Sanabria, R., Frankino, P. A., Paul, J. W., Tronnes, S. U., & Dillin, A. G. (2018) · Developmental Cell · doi:10.1016/j.devcel.2017.12.020 · Cited by 149 · see citing works
“A similar age-associated decline occurs in other quality control and stress response pathways, including UPRER, UPRMT, autophagy, and the ubiquitin proteasome system (Cuervo, 2008; Diot et al., 2015; Ekstrand et al., 2007; Taylor and Dillin, 2013; Vilchez et al., 2012).”
BackgroundResveratrol protects against peripheral deficits in a mouse model of Huntington's disease
Ho, D. J., Calingasan, N. Y., Wille, E. J., Dumont, M., & Beal, M. F. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.05.006 · Cited by 147 · see citing works
Mitochondrial DNA Mutations in Disease, Aging, and Neurodegeneration
Reeve, A. K., Krishnan, K. J., & Turnbull, D. M. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1427.016 · Cited by 146 · see citing works
The multilingual nature of dopamine neurons
Trudeau, L., Hnasko, T. S., Wallén‐Mackenzie, Å., Morales, M., Rayport, S., & Sulzer, D. L. (2014) · Progress in brain research · doi:10.1016/b978-0-444-63425-2.00006-4 · Cited by 138 · see citing works
“The cKO was carried out by using a DAT-Cre mouse (Ekstrand et al., 2007; Zhuang et al., 2005), which, based on the known developmental expression pattern of DAT, should drive Cre recombinase expression and gene deletion approximately by embryonic days 13 or 14 (Fujita et al.”
Panman, L., Papathanou, M., Laguna, A., Oosterveen, T., Volakakis, N., Acampora, D., Kurtsdotter, I., Yoshitake, T., Kehr, J., Joodmardi, E., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.016 · Cited by 143 · see citing works
“Sox6fl/+ animals (Dumitriu et al., 2006) were crossed with DatCre/+;Sox6fl/+ animals (Ekstrand et al., 2007) to obtainDatCre/+;Sox6fl/flmutant offspring.”
BackgroundStriatal Neuroinflammation Promotes Parkinsonism in Rats
Choi, D.-Y., Liu, M., Hunter, R. L., Cass, W. A., Pandya, J. D., Sullivan, P. G., Shin, E.-J., Kim, H.-C., Gash, D. M., & Bing, G. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005482 · Cited by 141 · see citing works
“Furthermore, mitochondrial dysfunction alone is sufficient to initiate parkinsonism in conditional knock-out mice by disrupting the gene for mitochondrial transcription factor A in the nigral dopamine neurons [39].”
Pi, H., Xu, S., Zhang, L., Guo, P., Li, Y., Xie, J., Tian, L., He, M., Lu, Y., Li, M., et al. (2013) · Autophagy · doi:10.4161/auto.25665 · Cited by 139 · see citing works
“Mitochondrial biogenesis is regulated by PPARGC1A and TFAM, which are responsible for initiating the synthesis of mtDNA-encoded respiratory chain proteins, such as the complex IV subunit.(29,30) However, in the present study, the expression of the transcription factor, PPARGC1A and that of its downstream target TFAM w…”
BackgroundA neural network for intermale aggression to establish social hierarchy
Stagkourakis, S., Spigolon, G., Williams, P., Protzmann, J., Fisone, G., & Broberger, C. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0153-x · Cited by 135 · see citing works
Mitochondrial Dysfunction and Parkinson’s Disease: Pathogenesis and Therapeutic Strategies
Vastegani, S. M., Nasrolahi, A., Ghaderi, S., Belali, R., Rashno, M., Farzaneh, M., & Khoshnam, S. E. (2023) · Neurochemical Research · doi:10.1007/s11064-023-03904-0 · Cited by 145 · see citing works
Mitochondria targeted therapeutic approaches in Parkinson's and Huntington's diseases
Chaturvedi, R. K., & Beal, M. F. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.11.011 · Cited by 139 · see citing works
Good, C. H., Hoffman, A. F., Hoffer, B. J., Chefer, V. I., Shippenberg, T. S., Bäckman, C. M., Larsson, N., Olson, L., Gellhaar, S., Galter, D., et al. (2011) · The FASEB Journal · doi:10.1096/fj.10-173625 · Cited by 134 · see citing works
Self-citationDisrupted iron homeostasis causes dopaminergic neurodegeneration in mice
Matak, P., Matak, A., Moustafa, S. M., Aryal, D. K., Benner, E. J., Wetsel, W. C., & Andrews, N. C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1519473113 · Cited by 133 · see citing works
“We observed proteinaceous inclusions in processes of Tfr1-CKO DA neurons, similar to those reported in DA neurons lacking autophagy protein Atg7 (52) or mitochondrial transcription factor Tfam (53).”
BackgroundEkstrand, M. I., & Galter, D. (2009) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(09)70811-9 · Cited by 134 · see citing works
“The observed neurodegeneration correlates well with direct neurochemical measurements of DA in different parts of the nigrostriatal system, as DA levels are much decreased in MitoPark mice compared to wild type littermates, especially in striatal areas [21].”
BackgroundInfluentialSelf-citationMitochondria at the interface between neurodegeneration and neuroinflammation
Bader, V., & Winklhofer, K. F. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.028 · Cited by 132 · see citing works
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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