References of "Burbulla, Lena F"
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See detailDopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.
Burbulla, Lena F.; Song, Pingping; Mazzulli, Joseph R. et al

in Science (New York, N.Y.) (2017), 357(6357), 1255-1261

Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains ... [more ▼]

Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and alpha-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or alpha-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis. [less ▲]

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See detailGenetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression.
Reinhardt, Peter; Schmid, Benjamin; Burbulla, Lena F. et al

in Cell Stem Cell (2013), 12(3), 354-67

The LRRK2 mutation G2019S is the most common genetic cause of Parkinson's disease (PD). To better understand the link between mutant LRRK2 and PD pathology, we derived induced pluripotent stem cells from ... [more ▼]

The LRRK2 mutation G2019S is the most common genetic cause of Parkinson's disease (PD). To better understand the link between mutant LRRK2 and PD pathology, we derived induced pluripotent stem cells from PD patients harboring LRRK2 G2019S and then specifically corrected the mutant LRRK2 allele. We demonstrate that gene correction resulted in phenotypic rescue in differentiated neurons and uncovered expression changes associated with LRRK2 G2019S. We found that LRRK2 G2019S induced dysregulation of CPNE8, MAP7, UHRF2, ANXA1, and CADPS2. Knockdown experiments demonstrated that four of these genes contribute to dopaminergic neurodegeneration. LRRK2 G2019S induced increased extracellular-signal-regulated kinase 1/2 (ERK) phosphorylation. Transcriptional dysregulation of CADPS2, CPNE8, and UHRF2 was dependent on ERK activity. We show that multiple PD-associated phenotypes were ameliorated by inhibition of ERK. Therefore, our results provide mechanistic insight into the pathogenesis induced by mutant LRRK2 and pointers for the development of potential new therapeutics. [less ▲]

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See detailA novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network.
Grau, Tanja; Burbulla, Lena F.; Engl, Gertraud et al

in Journal of medical genetics (2013), 50(12), 848-58

BACKGROUND: Mutations in OPA3 have been reported in patients with autosomal dominant optic atrophy plus cataract and Costeff syndrome. Here, we report the results of a comprehensive study on OPA3 ... [more ▼]

BACKGROUND: Mutations in OPA3 have been reported in patients with autosomal dominant optic atrophy plus cataract and Costeff syndrome. Here, we report the results of a comprehensive study on OPA3 mutations, including the mutation spectrum and its prevalence in a large cohort of OPA1-negative autosomal dominant optic atrophy (ADOA) patients, the associated clinical phenotype and the functional characterisation of a newly identified OPA3 mutant. METHODS: Mutation analysis was carried out in a patient cohort of 121 independent ADOA patients. To characterise a novel OPA3 mutation, we analysed the mitochondrial import, steady-state levels and the mitochondrial localisation of the mutated protein in patients' fibroblasts. Furthermore, the morphology of mitochondria harbouring the mutated OPA3 was monitored. RESULTS: We identified four independent cases (representing families with multiple affected members) with OPA3 mutations. Besides the known p.Q105E mutation, we observed a novel insertion, c.10_11insCGCCCG/p.V3_G4insAP which is located in the mitochondrial presequence. Detailed functional analysis of mitochondria harbouring this novel mutation demonstrates a fragmented mitochondrial network with a decreased mitochondrial mass in patient fibroblasts. In addition, quantification of the OPA3 protein reveals decreased steady-state levels of the mutant protein compared with the native one. Comparison of the clinical phenotypes suggests that OPA3 mutations can additionally evoke hearing loss and by that extend the clinical manifestation of OPA3-associated optic atrophy. This finding is supported by expression analysis of OPA3 in murine cochlear tissue. CONCLUSIONS: In summary, our study provides new insights into the clinical spectrum and the pathogenesis of dominant optic atrophy caused by mutations in the OPA3 gene. [less ▲]

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See detailKnockdown of Hsc70-5/mortalin induces loss of synaptic mitochondria in a Drosophila Parkinson's disease model.
Zhu, Jun-Yi; Vereshchagina, Natalia; Sreekumar, Vrinda et al

in PloS one (2013), 8(12), 83714

Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of ... [more ▼]

Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson's disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism. [less ▲]

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See detailGuidelines for the use and interpretation of assays for monitoring autophagy.
Klionsky, Daniel J.; Abdalla, Fabio C.; Abeliovich, Hagai et al

in Autophagy (2012), 8(4), 445-544

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field ... [more ▼]

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field. [less ▲]

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See detailThe use of primary human fibroblasts for monitoring mitochondrial phenotypes in the field of Parkinson's disease.
Burbulla, Lena F.; Krüger, Rejko UL

in Journal of visualized experiments : JoVE (2012), (68),

Parkinson's disease (PD) is the second most common movement disorder and affects 1% of people over the age of 60 (1). Because ageing is the most important risk factor, cases of PD will increase during the ... [more ▼]

Parkinson's disease (PD) is the second most common movement disorder and affects 1% of people over the age of 60 (1). Because ageing is the most important risk factor, cases of PD will increase during the next decades (2). Next to pathological protein folding and impaired protein degradation pathways, alterations of mitochondrial function and morphology were pointed out as further hallmark of neurodegeneration in PD (3-11). After years of research in murine and human cancer cells as in vitro models to dissect molecular pathways of Parkinsonism, the use of human fibroblasts from patients and appropriate controls as ex vivo models has become a valuable research tool, if potential caveats are considered. Other than immortalized, rather artificial cell models, primary fibroblasts from patients carrying disease-associated mutations apparently reflect important pathological features of the human disease. Here we delineate the procedure of taking skin biopsies, culturing human fibroblasts and using detailed protocols for essential microscopic techniques to define mitochondrial phenotypes. These were used to investigate different features associated with PD that are relevant to mitochondrial function and dynamics. Ex vivo, mitochondria can be analyzed in terms of their function, morphology, colocalization with lysosomes (the organelles degrading dysfunctional mitochondria) and degradation via the lysosomal pathway. These phenotypes are highly relevant for the identification of early signs of PD and may precede clinical motor symptoms in human disease-gene carriers. Hence, the assays presented here can be utilized as valuable tools to identify pathological features of neurodegeneration and help to define new therapeutic strategies in PD. [less ▲]

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See detailConverging environmental and genetic pathways in the pathogenesis of Parkinson's disease.
Burbulla, Lena F.; Krüger, Rejko UL

in Journal of the neurological sciences (2011), 306(1-2), 1-8

As a prototypic neurodegenerative disorder Parkinson's disease (PD) is characterized by the progressive loss of specific neuronal subpopulations leading to a late-onset movement disorder. Based on ... [more ▼]

As a prototypic neurodegenerative disorder Parkinson's disease (PD) is characterized by the progressive loss of specific neuronal subpopulations leading to a late-onset movement disorder. Based on familial forms of PD, to date a significant number of genes were identified that allowed first insight into the molecular pathogenesis of this common movement disorder. These pathways include impaired protein degradation and subsequent aggregation within neuronal cells and impaired mitochondrial function followed by energy depletion due to oxidative stress leading to cell death. The respective disease models were supported by pathoanatomical and biochemical findings in brains of sporadic PD patients without apparent genetic contribution to pathogenesis. Indeed recent genetic and epidemiological studies hint to a complex interplay of genetic susceptibility factors and environmental risk factors to converge to processes of pathological protein accumulation and mitochondrial damage that trigger neurodegeneration in PD. Therefore large-scale geneticoepidemiological studies combining genetic whole genome approaches with a detailed ascertainment of environmental exposures are expected to provide important clues to decipher the complexity of neurodegeneration of this most frequent neurodegenerative movement disorder. [less ▲]

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See detailDissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis.
Burbulla, Lena F.; Schelling, Carina; Kato, Hiroki et al

in Human molecular genetics (2010), 19(22), 4437-52

The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the ... [more ▼]

The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD. [less ▲]

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See detailReduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1.
Krebiehl, Guido; Ruckerbauer, Sabine; Burbulla, Lena F. et al

in PloS one (2010), 5(2), 9367

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD ... [more ▼]

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. CONCLUSIONS/SIGNIFICANCE: We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease. [less ▲]

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See detailBalance is the challenge--the impact of mitochondrial dynamics in Parkinson's disease.
Burbulla, Lena F.; Krebiehl, Guido; Krüger, Rejko UL

in European journal of clinical investigation (2010), 40(11), 1048-60

Impaired mitochondrial function has been implicated in neurodegeneration in Parkinson's disease (PD) based on biochemical and pathoanatomical studies in brains of PD patients. This observation was further ... [more ▼]

Impaired mitochondrial function has been implicated in neurodegeneration in Parkinson's disease (PD) based on biochemical and pathoanatomical studies in brains of PD patients. This observation was further substantiated by the identification of exogenic toxins, i.e. complex I inhibitors that directly affect mitochondrial energy metabolism and cause Parkinsonism in humans and various animal models. Recently, insights into the underlying molecular signalling pathways leading to alterations in mitochondrial homeostasis were gained based on the functional characterization of mitoprotective genes identified in rare forms of inherited PD. Using in vitro and in vivo loss of function models of the Parkin, PINK1, DJ-1 and Omi/HtrA2 gene, the emerging field of mitochondrial dynamics in PD was established as being critical for the maintenance of mitochondrial function in neurons. This underscored the concept that mitochondria are highly dynamic organelles, which are tightly regulated to continuously adapt shape to functional and anatomical requirements during axonal transport, synaptic signalling, organelle degradation and cellular energy supply. The dissection of pathways involved in mitochondrial quality control clearly established the PINK1/Parkin-pathway in the clearance of dysfunctional mitochondria by autophagy and hints to a complex interplay between PD-associated proteins acting at the mitochondrial interface. The elucidation of this mitoprotective signalling network may help to define novel therapeutic targets for PD via molecular modelling of mitochondria and/or pharmacological modulation of mitochondrial dynamics. [less ▲]

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