Ellen Nollen

Ellen Nollen
University of Groningen | RUG · Department of Genetics

About

85
Publications
23,938
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5,480
Citations
Citations since 2017
45 Research Items
3265 Citations
20172018201920202021202220230200400600
20172018201920202021202220230200400600
20172018201920202021202220230200400600
20172018201920202021202220230200400600

Publications

Publications (85)
Article
Aging is an important risk factor for many debilitating diseases, including cancer and neurodegeneration. In model organisms, interfering with metabolic signaling pathways, including the insulin/insulin-like growth factor (IGF) 1 (IIS) and TOR pathways, can protect against age-related pathologies and increase lifespan. Recent studies in multiple or...
Article
Full-text available
Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer’s diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity i...
Article
Full-text available
The inherent cytotoxicity of aberrantly folded protein aggregates contributes substantially to the pathogenesis of amyloid diseases. It was recently shown that a class of evolutionary conserved proteins, called MOAG-4/SERF, profoundly alter amyloid toxicity via an autonomous but yet unexplained mode. We show that the biological function of human SE...
Article
Background Fibrillar protein aggregates are the major pathological hallmark of several incurable, age related, neurodegenerative disorders. These aggregates typically contain aggregation prone pathogenic proteins, such as amyloid-β in Alzheimer's disease and α-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates...
Article
Inclusions consisting of transactive response DNA-binding protein 43 (TDP-43) are a characteristic and toxic feature of numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) (Arai et al., 2006; Neumann et al., 2006; Neumann et al., 2009). The small nematode Caenorhabditis elegans has been instrumental in studying the un...
Article
Cytoplasmic inclusions consisting of transactive response DNA-binding protein 43 (TDP-43) are a key hallmark of TDP-43 proteinopathies like amyotrophic lateral sclerosis (ALS). Caenorhabditis elegans is considered a useful model for studying the molecular mechanisms underlying TDP-43 toxicity in vivo . Here, we assessed different neuronal systems t...
Article
Transactive response DNA binding-protein 43 (TDP-43) is a conserved RNA/DNA-binding protein with a role in RNA metabolism and homeostasis. Aberrant TDP-43 functioning has been considered a major culprit in amyotrophic lateral sclerosis (ALS). Caenorhabditis elegans can be used to phenocopy ALS in vivo . Since disrupted locomotion is a strong readou...
Article
Inclusions consisting of transactive response DNA-binding protein 43 (TDP-43) are a characteristic feature of amyotrophic lateral sclerosis (ALS). Caenorhabditis elegans has been instrumental in studying the underlying mechanisms of TDP-43 pathology. Here, we extend the possibilities of previous studies by examining a C. elegans model expressing hu...
Preprint
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To maintain genome integrity, cells rely on a complex system of DNA repair pathways and cell cycle checkpoints, together referred to as the DNA damage response (DDR). Impairments in DDR pathways are linked to cancer, but also to a wide range of degenerative processes, frequently including progressive neuropathy and accelerated aging. How defects in...
Article
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While aggregation-prone proteins are known to accelerate aging and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A, and SERF2 have recently been identified as cellular modifiers of such proteotoxicity. Using a peptide array screening approach on human amylo...
Article
Full-text available
Background Optogenetics allows the experimental manipulation of excitable cells by a light stimulus without the need for technically challenging and invasive procedures. The high degree of spatial, temporal, and intensity control that can be achieved with a light stimulus, combined with cell type-specific expression of light-sensitive ion channels,...
Preprint
Full-text available
Optogenetic tools have revolutionized the study of neuronal circuits in Caenorhabditis elegans. The expression of light-sensitive ion channels or pumps under specific promotors allows researchers to modify the behavior of excitable cells. Several optogenetic systems have been developed to spatially and temporally photoactivate light-sensitive actua...
Article
Full-text available
Proteome damage plays a major role in aging and age-related neurodegenerative diseases. Under healthy conditions, molecular quality control mechanisms prevent toxic protein misfolding and aggregation. These mechanisms include molecular chaperones for protein folding, spatial compartmentalization for sequestration, and degradation pathways for the r...
Article
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The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while t...
Preprint
Full-text available
Loss of protein homeostasis accelerates ageing and contributes to age-related brain diseases like Parkinson’s and Alzheimer’s diseases. Disease-specific proteins become aggregation-prone and form amyloid deposits that characterize disease, but the biological mechanisms driving their transition in cells and tissues are poorly understood. MOAG-4/SERF...
Article
Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson’s disease. A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here we show, both in vitro and in a Caenorhabditis elegans model...
Preprint
While aggregation-prone proteins are known to accelerate ageing and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A and SERF2 have recently been identified as cellular modifiers of such cytotoxicity. Using a peptide array screening approach on human amyloid...
Preprint
Full-text available
Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson's disease. A large body of evidence shows that α-synuclein can self-assemble into amyloid fibrils, but the relationship between amyloid formation and Lewy body formation still remains unclear. Here we show, both in vitro and in a C. elegans model of Parkins...
Article
Full-text available
Caenorhabditis elegans is a valuable model organism in biomedical research that has led to major discoveries in the fields of neurodegeneration, cancer and aging. Because movement phenotypes are commonly used and represent strong indicators of C. elegans fitness, there is an increasing need to replace manual assessments of worm motility with automa...
Article
Cells are protected from endoplasmic reticulum stress through the unfolded protein response (UPR). In this issue of Cell, Schinzel, Higuchi-Sanabria, Shalem et al., identify a mechanism that helps cells cope with ER stress but is independent of canonical UPR activation, instead involving the extracellular matrix hyaluronidase, TMEM2, as a signaling...
Article
Full-text available
Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammat...
Article
The nematode worm Caenorhabditis elegans has emerged as an important model organism to study the molecular mechanisms of protein misfolding diseases associated with amyloid formation because of its small size, ease of genetic manipulation and optical transparency. Obtaining a reliable and quantitative read-out of protein aggregation in this system,...
Article
Full-text available
Aging strongly influences human morbidity and mortality. Thus, aging-preventive compounds could greatly improve our health and lifespan. Here we screened for such compounds, known as geroprotectors, employing the power of transcriptomics to predict biological age. Using age-stratified human tissue transcriptomes and machine learning, we generated a...
Chapter
Caenorhabditis elegans is widely used to investigate biological processes related to health and disease. Multiple C. elegans models for human neurodegenerative diseases do exist, including those expressing human α-synuclein. Even though these models do not feature all pathological and molecular hallmarks of the disease they mimic, they allow for th...
Article
l-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzyme...
Article
Caenorhabditis elegans is a well-established animal model in biomedical research, widely employed in functional genomics and ageing studies. To assess the health and fitness of the animals under study, one typically relies on motility readouts, such as the measurement of the number of body bends or the speed of movement. These measurements usually...
Preprint
Aging is a major risk factor for human morbidity and mortality. Thus, the identification of compounds that defer aging, also known as 'geroprotectors', could greatly improve our health and promote a longer life. Here we screened for geroprotectors, employing the power of human transcriptomics to predict biological age. We used age-stratified human...
Article
C. elegans is widely used to investigate biological processes related to health and disease. To study protein localization, fluorescently-tagged proteins can be used in vivo or immunohistochemistry can be performed in whole worms. Here, we describe a technique to localize a protein of interest at a subcellular level in C. elegans lysates, which can...
Article
Protein aggregation is a hallmark of several neurodegenerative diseases and is associated with impaired protein homeostasis. This imbalance is caused by the loss of the protein's native conformation, which ultimately results in its aggregation or abnormal localization within the cell. Using a C. elegans model of polyglutamine diseases, we describe...
Preprint
Full-text available
The nematode worm Caenorhabditis elegans has emerged as an important model organism to study the molecular mechanisms of protein misfolding diseases associated with amyloid formation because of its small size, ease of genetic manipulation, and optical transparency. Obtaining a reliable and quantitative read-out of protein aggregation in this system...
Article
BACKGROUND: The nematode worm C. elegans is a model organism widely used for studies of genetics and of human disease. The health and fitness of the worms can be quantified in different ways, such as by measuring their bending frequency, speed or lifespan. Manual assays, however, are time consuming and limited in their scope providing a strong moti...
Article
The aggregation of α-synuclein, an intrinsically disordered protein that is highly abundant in neurons, is closely associated with the onset and progression of Parkinson’s disease. We have shown previously that the aminosterol squalamine can inhibit the lipid induced initiation process in the aggregation of α-synuclein, and we report here that the...
Article
Background: The nematode worm C. elegans is a model organism widely used for studies of genetics and of human disease. The health and fitness of the worms can be quantified in different ways, such as by measuring their bending frequency, speed or lifespan. Manual assays, however, are time consuming and limited in their scope providing a strong mot...
Article
Full-text available
Aberrant protein aggregation underlies a variety of age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Little is known, however, about the molecular mechanisms that modulate the aggregation process in the cellular environment. Recently, MOAG-4/SERF has been identified as a class of evolutionarily conserved prot...
Article
Full-text available
Protein aggregation is associated with age-related neurodegenerative disorders, such as Alzheimer’s and polyglutamine diseases. As a causal relationship between protein aggregation and neurodegeneration remains elusive, understanding the cellular mechanisms regulating protein aggregation will help develop future treatments. To identify such mechani...
Data
Table S3. Analysis of Differential Expression between Q40 and Q40;moag-2/lir-3 Mutants Related to Figures 4 and S4. This table includes raw data showing the changes in transcription between Q40 and Q40;moag-2/lir-3 mutants in Figures 4 and S4.
Data
Related to Figures 1, 4, S4, and S5. This table includes raw data showing the average number of aggregates and p values for the panel(s) in Figures 1, 4, S4, and S5.
Article
Full-text available
As the population is aging, the incidence of age-related neurodegenerative diseases, such as Alzheimer and Parkinson disease, is growing. The pathology of neurodegenerative diseases is characterized by the presence of protein aggregates of disease specific proteins in the brain of patients. Under certain conditions these disease proteins can underg...
Article
Full-text available
Background Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson’s disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Ca...
Article
Full-text available
Significance Parkinson’s disease is characterized by the presence in brain tissues of aberrant aggregates primarily formed by the protein α-synuclein. It has been difficult, however, to identify compounds capable of preventing the formation of such deposits because of the complexity of the aggregation process of α-synuclein. By exploiting recently...
Article
Full-text available
The enzyme TDO (tryptophan 2,3-dioxygenase; TDO-2 in Caenorhabditis elegans) is a potential therapeutic target to cancer but is also thought to regulate proteotoxic events seen in the progression of neurodegenerative diseases. To better understand its function and develop specific compounds that target TDO we need to understand the structure of thi...
Article
Mitochondrial dysfunction is at the core of many diseases ranging from inherited metabolic diseases to common conditions that are associated with aging. Although associations between aging and mitochondrial function have been identified using mammalian models, much of the mechanistic insight has emerged from Caenorhabditis elegans. Mitochondrial re...
Article
Full-text available
The balance between protein synthesis and protein breakdown is a major determinant of protein homeostasis, and loss of protein homeostasis is one of the hallmarks of aging. Here we describe pulsed SILAC-based experiments to estimate proteome-wide turnover rates of individual proteins. We applied this method to determine protein turnover rates in Ca...
Article
Full-text available
The conversion of the ?-amyloid (A?) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer?s disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of A? or inhibit its aggregation, all clinical trials with these objectives have so far failed, at leas...
Article
Full-text available
The metabolic cofactor coenzyme A (CoA) gained renewed attention because of its roles in neurodegeneration, protein acetylation, autophagy and signal transduction. The long-standing dogma is that eukaryotic cells obtain CoA exclusively via the uptake of extracellular precursors, especially vitamin B5, which is intracellularly converted through five...
Article
Full-text available
Protein homeostasis is fundamental for cell function and survival, because proteins are involved in all aspects of cellular function, ranging from cell metabolism and cell division to the cell's response to environmental challenges. Protein homeostasis is tightly regulated by the synthesis, folding, trafficking and clearance of proteins, all of whi...
Article
Full-text available
Caenorhabditis elegans comprises unique features that make it an attractive model organism in diverse fields of biology. Genetic screens are powerful to identify genes and C. elegans can be customized to forward or reverse genetics screens and to establish gene function. These genetic screens can be applied to "humanized" models of C. elegans for n...
Article
The accumulation of specific aggregation-prone proteins during aging is thought to be involved in several diseases, most notably Alzheimer's and Parkinson's disease as well as polyglutamine expansion disorders such as Huntington's disease. Caenorhabditis elegans disease models with transgenic expression of fluorescently tagged aggregation-prone pro...
Article
Toxicity of aggregation-prone proteins is thought to play an important role in ageing and age-related neurological diseases like Parkinson's and Alzheimer's disease. Here we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity...
Article
Full-text available
Pantothenate kinase-associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transferred to lysine residues of proteins, in a reaction...
Article
Protein aggregation is a common hallmark of a number of age-related neurodegenerative diseases, including Alzheimer's, Parkinson's, and polyglutamine-expansion disorders such as Huntington's disease, but how aggregation-prone proteins lead to pathology is not known. Using a genome-wide RNAi screen in a C. elegans-model for polyglutamine aggregation...
Article
Misfolding and aggregation of amyloidogenic polypeptides lie at the root of many neurodegenerative diseases. Whilst protein aggregation can be readily studied in vitro by established biophysical techniques, direct observation of the nature and kinetics of aggregation processes taking place in vivo is much more challenging. We describe here, however...
Chapter
The free living nematode worm Caenorhabditis elegans (C. elegans) has been extensively studied by biological, agricultural, and medical scientists for over 40 years. The animal has several characteristics that make it useful as a model organism. For example, the nematodes are transparent, which allows study of embryonic development and gene express...
Article
Misfolding and aggregation of proteins are characteristics of a range of increasingly prevalent neurodegenerative disorders including Alzheimer's and Parkinson's diseases. In Parkinson's disease and several closely related syndromes, the protein alpha-synuclein (AS) aggregates and forms amyloid-like deposits in specific regions of the brain. Fluore...
Article
Various age-related neurodegenerative diseases, including Parkinson's disease, polyglutamine expansion diseases and Alzheimer's disease, are associated with the accumulation of misfolded proteins in aggregates in the brain. How and why these proteins form aggregates and cause disease is still poorly understood. Small model organisms--the baker's ye...
Article
Full-text available
The ATP-dependent protein chaperone heat-shock protein 70 (Hsp70) displays broad anti-aggregation functions and has a critical function in preventing protein misfolding pathologies. According to in vitro and in vivo models of Parkinson's disease (PD), loss of Hsp70 activity is associated with neurodegeneration and the formation of amyloid deposits...
Article
Full-text available
Inclusions in the brain containing alpha-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a C. elegans model that makes it possible to monitor, in living animals, the formation of alpha-synuclein inclusions. In worms of old age,...
Article
Full-text available
Here, we describe a systematic search for synthetic gene interactions in a multicellular organism, the nematode Caenorhabditis elegans. We established a high-throughput method to determine synthetic gene interactions by genome-wide RNA interference and identified genes that are required to protect the germ line against DNA double-strand breaks. Bes...