Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo

201

175

Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death. Recently, the parkin interacting substrate (PARIS) also known as zinc finger protein 746 (ZNF746) was shown to be required for loss of DA neurons in adult conditional parkin knockout (KO) mice (19). PARIS is polyubiquitinated by parkin via lysine-48 targeting it for ubiquitin proteasomal degradation. Deletion of parkin in adult mice leads to an age-dependent progressive loss of DA neurons that is due to the accumulation of PARIS because depletion of PARIS in adult conditional parkin knockout mice prevents the loss of DA neurons (19). PARIS is a transcriptional repressor that regulates the expression of peroxisome proliferator-activated receptor gamma, coactivator 1α (PGC-1α), a master coregulator of mitochondrial function, biogenesis, and mitochondrial oxidative stress management (19,20). In adult conditional parkin knockout mice, there is a reduction in PGC-1α levels that is dependent on PARIS because reduction in PARIS reverses the reduction in PGC-1α levels (19). PARIS overexpression, at levels equivalent to those in the adult conditional parkin knockout mice, also leads to defects in PGC-1α and causes the selective loss of DA neurons (19). PGC-1α overexpression prevents the defects in PGC-1α signaling and the loss of DA neurons, suggesting that PARIS kills DA neurons in a PGC-1α-dependent fashion (19).Because PGC-1α is a master coregulator of mitochondrial function and mitochondrial defects are a consistent feature of PD, mitochondria were assessed in the adult conditional parkin knockout mice. Here we show that adult conditional knockout of parkin leads to reductions in mitochondrial mass that are dependent upon PARIS. Moreover, PARIS accumulation leads to substantial deficits in mitochondrial respiration that are PGC-1α dependent. Our findings are consistent with parkin regulation of mitochondrial biogenesis. ResultsReduced Mitochondrial Size and Number in Adult Conditional Parkin Knockouts. Adult conditional parkin knockout mice were generated as previously described by injecting a lentiviru...

Section: Discussionmentioning

confidence: 99%

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration

Stevens

Kang

Lee

et al. 2015

201

175

“…S4). We crossed Tfr1-CKO mice with mtYFP transgenic mice that express a mitochondria-targeted GFP in the presence of Cre recombinase (32). Tfr1-CKO mitochondria appeared fused or aggregated in SNpc DA neurons ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Ribotag transgenic mice (B6N.129-Rpl22 tm1.1Psam /J; stock no: 011029) (28) were obtained from Jackson Laboratory. mtYFP mice were kindly provided by Nils-Göran Larsson (Max Planck Institute, Cologne, Germany) (32). The Duke Institutional Animal Care and Use Committee approved all animal studies.…”

Section: Methodsmentioning

confidence: 99%

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Matak

Moustafa

et al. 2016

105

Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.iron | transferrin receptor | ferroportin | dopaminergic neuron | neurodegeneration

“…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%

Mitochondrial retrograde signaling regulates neuronal function

Cagin

Duncan

Gatt

et al. 2015

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.