Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons

Ekstrand, Mats I.; Terzioglu, Mügen; Galter, Dagmar; Zhu, Shunwei; Hofstetter, Christoph P.; Lindqvist, Eva; Thams, Sebastian; Bergstrand, A; Hansson, Fredrik; Trifunović, Aleksandra; Hoffer, Barry J.; Cullheim, Staffan; Mohammed, Abdul K.; Olson, Lar̀s; Larsson, Nils‐Göran

doi:10.1073/pnas.0605208103

Cited by 536 publications

(540 citation statements)

References 35 publications

Supporting

Mentioning

518

Contrasting

Unclassified

Order By: Relevance

“…In keeping with these findings, increased exposure of the mitochondrial genome to TFAM has been reported to enhance 7S DNA association and mtDNA replication in an in organello DNA synthesis system 32. 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 effect as a CI inhibitor, the PD‐inducing reagent 1 methyl‐4‐phenylpyridinium also interferes with mtDNA replication by destabilization of the mitochondrial D‐loop 35, 36.…”

Section: Discussionsupporting

confidence: 89%

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Grünewald

Rygiel

Hepplewhite

et al. 2016

Annals of Neurology

207

162

View full text Add to dashboard Cite

ObjectiveTo determine the extent of respiratory chain abnormalities and investigate the contribution of mtDNA to the loss of respiratory chain complexes (CI–IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single‐neuron level.MethodsMultiple‐label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI–IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2, and COXI) and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser‐capture microdissection, were assayed for mtDNA deletions, copy number, and presence of transcription/replication‐associated 7S DNA employing a triplex real‐time polymerase chain reaction (PCR) assay.ResultsWhereas mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At the single‐cell level, CI and II deficiencies were correlated in patients. The CI deficiency concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription‐primed mtDNA replication. Consistent with this, real‐time PCR analysis revealed fewer transcription/replication‐associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe CI deficiency.InterpretationRespiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA‐encoded factors mechanistically connected via TFAM. ANN NEUROL 2016;79:366–378

show abstract

Section: Discussionsupporting

confidence: 89%

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Grünewald

Rygiel

Hepplewhite

et al. 2016

Annals of Neurology

207

162

View full text Add to dashboard Cite

show abstract

“…A way to analyze this role is by removing Vglut2 expression by gene-targeted mutation specifically in the DA neurons of mice. We produced such a conditional knockout by crossing our Vglut2 f/f mice, generated and validated previously in our laboratory (10,12), with transgenic DAT-Cre mice (16). Our analysis of the basal behavior of the mice did not show any major differences in motor coordination or memory function between the Vglut2 f/f;DAT-Cre and littermate control mice, but the Vglut2 f/f;DAT-Cre mice showed altered risk-taking behavior.…”

Section: Discussionmentioning

confidence: 99%

“…A DA transporter (DAT)-Cre transgenic mouse, produced by homologous recombination into the endogenous DAT locus (16), was characterized to ensure the DAT-Cre function. The production of this Cre mouse included restoration of the DAT gene after insertion of the Cre cassette (Fig.…”

Section: Resultsmentioning

confidence: 99%

VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation

Birgner

Nordenankar

Lundblad

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

119

151

View full text Add to dashboard Cite

The "One neuron-one neurotransmitter" concept has been challenged frequently during the last three decades, and the coexistence of neurotransmitters in individual neurons is now regarded as a common phenomenon. The functional significance of neurotransmitter coexistence is, however, less well understood. Several studies have shown that a subpopulation of dopamine (DA) neurons in the ventral tegmental area (VTA) expresses the vesicular glutamate transporter 2 (VGLUT2) and has been suggested to use glutamate as a cotransmitter. The VTA dopamine neurons project to limbic structures including the nucleus accumbens, and are involved in mediating the motivational and locomotor activating effects of psychostimulants. To determine the functional role of glutamate cotransmission by these neurons, we deleted VGLUT2 in DA neurons by using a conditional gene-targeting approach in mice. A DAT-Cre/Vglut2Lox mouse line (Vglut2 f/f;DAT-Cre mice) was produced and analyzed by in vivo amperometry as well as by several behavioral paradigms. Although basal motor function was normal in the Vglut2 f/f;DAT-Cre mice, their risk-taking behavior was altered. Interestingly, in both home-cage and novel environments, the gene targeted mice showed a greatly blunted locomotor response to the psychostimulant amphetamine, which acts via the midbrain DA system. Our results show that VGLUT2 expression in DA neurons is required for normal emotional reactivity as well as for psychostimulant-mediated behavioral activation.amphetamine | midbrain | neurotransmission | reward | striatum

show abstract

“…Knockout of TFAM specifically in mouse dopaminergic neurons (the "MitoPark" mouse model) causes progressive loss of motor function, intraneuronal inclusions, and eventual neuronal cell death (38,40). Interestingly, cell body mitochondria are enlarged and fragmented and striatal mitochondria are reduced in number and size in MitoPark dopaminergic neurons (41), suggesting that the effects of neuronal mitochondrial dysfunction are conserved in Drosophila and mammals.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies in mice have examined the effects of neuronal mitochondrial dysfunction by using mitoPstI expression, or targeted knockout of TFAM (38,39). Knockout of TFAM specifically in mouse dopaminergic neurons (the "MitoPark" mouse model) causes progressive loss of motor function, intraneuronal inclusions, and eventual neuronal cell death (38,40).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial retrograde signaling regulates neuronal function

Cagin

Duncan

Gatt

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson’s disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.

show abstract

Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons

Cited by 536 publications

References 35 publications

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation

Mitochondrial retrograde signaling regulates neuronal function

Contact Info

Product

Resources

About