The mitochondrial kinase PINK1, stress response and Parkinson’s disease

Jendrach, Marina; Gispert, Suzana; Ricciardi, Filomena; Klinkenberg, Michael; Schemm, Rudolf; Auburger, Georg

doi:10.1007/s10863-009-9256-0

Cited by 32 publications

(18 citation statements)

References 66 publications

(76 reference statements)

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“…In contrast, our data show very clear and consistent expression anomalies and mitochondrial pathology under distinct deprivation conditions, probably due to the fact that the function of PINK1 and Parkin is part of a quality control pathway that becomes relevant only under stress conditions [27–29]. …”

Section: Identification Of Potential Biomarkers For Diagnostics In Skmentioning

confidence: 88%

Primary Skin Fibroblasts as a Model of Parkinson's Disease

et al. 2012

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Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems.

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Section: Identification Of Potential Biomarkers For Diagnostics In Skmentioning

confidence: 88%

Primary Skin Fibroblasts as a Model of Parkinson's Disease

et al. 2012

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“…The lighter and sustained energy disturbance induced in the chronic model may have favored damage to the energy producing ability of energy sensitive DA cells and accumulated in them; whereas in the acute model, the severe energy disturbance was beyond the compensation ability of the tissues, therefore selective damage of DA cells was not induced. Therefore, future research into how the fragile cells were regulated to confront the energy stress may aid the elucidation of the underlying mechanisms of PD, which would build upon previous studies that have indicated PD-associated genes, parkin, phosphatase and tensin homolog-induced novel kinase-1 and DJ-1, are involved in energy crisis (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Rotenone-induced energy stress decompensated in ventral mesocerebrum is associated with Parkinsonism progression in rats

Bai

Tang³

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is characterized by the hallmark feature of loss of dopaminergic neurons in the substantia nigra. Energy metabolic disorder is associated with the pathogenesis of PD; however, the development of this disorder is yet to be elucidated. PD-like characteristics have been demonstrated in a rotenone rat model. In the present study, energy metabolism status was investigated in a rat model following intraperitoneal treatment with 1.0 mg/kg rotenone every 48 h. The behavior and tyrosine hydroxylase-positive levels in the substantia nigra of rats that were treated with rotenone for 24 weeks demonstrated that these rats developed more severe parkinsonism, as compared with that were treated for 16 weeks. Detection of ATP, lactic acid, NADH dehydrogenase 1 mRNA and lactate dehydrogenase B mRNA levels in the ventral mesocerebrum (VM) and skeletal muscle (SM) of the rats that had been treated with rotenone for 16 and 24 weeks demonstrated that the energy stress induced by rotenone progressed in both VM and SM. Notably, the energy stress detected in VM was more severe, and this energy stress was decompensated in the VM of rats that had been treated with rotenone for 24 weeks. The progression of energy stress and the incidence of energy decompensation in VM may be important for the improvement of PD pathology. IntroductionParkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra. PD is the most common neurodegenerative movement disorder, affecting >1% of the population that are aged >60 (1). Current treatments, such as pharmaceutical agents or deep brain stimulation predominantly target the symptoms and are unable to attenuate or reverse the progression of this disease (2). Understanding PD at a cellular and molecular level is important to determine novel targets and develop neuroprotective and disease-modifying therapeutic strategies. Although the causes and potential factors remain unknown, environmental factors may have a critical role, such as herbicides or pesticides, organic solvents, carbon monoxide and carbon disulfide (3,4). Notably, various studies have suggested that PD is associated with energy metabolism defects (5-7).Due to their structure, physiologic activities and high oxidative level of DA metabolism, DA cells in the substantia nigra are energy demanding and prone to energy stress (8). Furthermore, these cells have a relative low capacity for glycolysis compensation and lower glutathione levels (9,10), which ensures that they cannot respond appropriately to energy stress and are thus sensitive to energy disturbances.Rotenone is a common insecticide and mitochondria complex 1 inhibitor, which is used to induce chronic rotenone rat models with PD-associated features that manifest as DA cells are selectively damaged (11). However, how energy stress is induced and associated with the development of PD-associated in this model remains unknown.In the present study, rats were ...

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“…The PD-associated protein known as PINK1, or PTEN-induced kinase 1, is a mitochondrial-targeted protein that contains a highly conserved serine/threonine kinase domain 9 . Homozygous mutations in pink1 are also connected to autosomal recessive, early-onset PD 10 .…”

Section: Introductionmentioning

confidence: 99%

The effects of pdr1, djr1.1 and pink1 loss in manganese-induced toxicity and the role of α-synuclein in C. elegans

et al. 2014

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Parkinson's disease (PD) is a neurodegenerative brain disorder characterized by selective dopaminergic (DAergic) cell loss that results in overt motor and cognitive deficits. Current treatment options exist to combat PD symptomatology, but are unable to directly target its pathogenesis due to a lack of knowledge concerning its etiology. Several genes have been linked to PD, including three genes associated with an early-onset familial form: parkin, pink1 and dj1. All three genes are implicated in regulating oxidative stress pathways. Another hallmark of PD pathophysiology is Lewy body deposition, associated with the gain-of-function genetic risk factor α-synuclein. The function of α-synuclein is poorly understood, as it shows both neurotoxic and neuroprotective activities in PD. Using the genetically tractable invertebrate Caenorhabditis elegans (C. elegans) model system, the neurotoxic or neuroprotective role of α-synuclein upon acute Mn exposure in the background of mutated pdr1, pink1 or djr1.1 was examined. The pdr1 and djr1.1 mutants showed enhanced Mn accumulation and oxidative stress that was rescued by α-synuclein. Moreover, DAergic neurodegeneration, while unchanged with Mn exposure, returned to wild-type (WT) levels for pdr1, but not djr1.1 mutants expressing α-synuclein. Taken together, this study uncovers a novel, neuroprotective role for WT human α-synuclein in attenuating Mn-induced toxicity in the background of PD-associated genes, and further supports the role of extracellular dopamine in exacerbating Mn neurotoxicity.

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The mitochondrial kinase PINK1, stress response and Parkinson’s disease

Cited by 32 publications

References 66 publications

Primary Skin Fibroblasts as a Model of Parkinson's Disease

Primary Skin Fibroblasts as a Model of Parkinson's Disease

Rotenone-induced energy stress decompensated in ventral mesocerebrum is associated with Parkinsonism progression in rats

The effects of pdr1, djr1.1 and pink1 loss in manganese-induced toxicity and the role of α-synuclein in C. elegans

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