Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases

Sin, Olga; Michels, Helen; Nollen, Ellen A. A.

doi:10.1016/j.bbadis.2014.01.015

Cited by 56 publications

(40 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This view is supported by the observation that disease manifestation in mice expressing aggregation prone mutant proteins is fully attenuated by switching the genetic background to that of a different mouse strain 110,111 , signifying that the intrinsic proteotoxicity of mutant proteins can be outweighed or promoted by additional genetic factors. Genetic screens in model organisms have revealed some of the factors that modulate proteotoxicity; many of these factors are proteins at the core of the proteo stasis network (reviewed previously 112,113 ). Given that some of these proteins are ubiquitously expressed, and because of similarities between neurons and cardio myocytes (both are terminally differentiated cell types with high metabolism), proteopathies conceivably confer a car diac risk as well.…”

Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

136

126

View full text Add to dashboard Cite

The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

show abstract

Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

136

126

View full text Add to dashboard Cite

show abstract

“…Forward genetic screens have been performed in various multicellular organisms such as plants (Meinke and Sussex, 1979), flies (Nusslein-Volhard and Wieschaus, 1980), worms (Sin et al, 2014), zebrafish , and mice (Hrabe de Angelis et al, 2000;Nolan et al, 2000) and have been very successful in discovering genes involved in embryonic patterning, organ development, and behavior (Horvitz, 1999;Muto et al, 2005;Stemple and Driever, 1996). The genetic plant model Arabidopsis thaliana, is a useful model system due to its small genome and minor amount of repetitive sequences (Page and Grossniklaus, 2002).…”

Section: Chapter 3 Forward Genetic Screen Identifies Choroid Plexus mentioning

confidence: 99%

Functional and Genetic Analysis of Choroid Plexus Development in Zebrafish

Henson¹

View full text Add to dashboard Cite

“…In fact, many human neurodegenerative diseases can be modeled at the C. elegans neuromuscular junction (NMJ) including Alzheimer’s disease, PD and ALS 39,42 . High-throughput electrophysiology would enable large-scale screens for drugs that effectively treat C. elegans models for neurological disease and could lead to improved treatments for human disorders 39,40,43 .…”

Section: Phenotyping Neurological Disease Modelsmentioning

confidence: 99%

Scalable electrophysiology in intact small animals with nanoscale suspended electrode arrays

et al. 2017

View full text Add to dashboard Cite

Electrical measurements from large populations of animals would help reveal fundamental properties of the nervous system and neurological diseases. Small invertebrates are ideal for these large-scale studies; however, patch-clamp electrophysiology in microscopic animals typically requires low-throughput and invasive dissections. To overcome these limitations, we present nano-SPEARs: suspended electrodes integrated into a scalable microfluidic device. Using this technology, we have made the first extracellular recordings of body-wall muscle electrophysiology inside an intact roundworm, Caenorhabditis elegans. We can also use nano-SPEARs to record from multiple animals in parallel and even from other species, such as Hydra littoralis. Furthermore, we use nano-SPEARs to establish the first electrophysiological phenotypes for C. elegans models for Amyotrophic Lateral Sclerosis and Parkinson’s disease, and show a partial rescue of the Parkinson’s phenotype through drug treatment. These results demonstrate that nano-SPEARs provide the core technology for microchips that enable scalable, in vivo studies of neurobiology and neurological diseases.

show abstract

Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases

Cited by 56 publications

References 109 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

Functional and Genetic Analysis of Choroid Plexus Development in Zebrafish

Scalable electrophysiology in intact small animals with nanoscale suspended electrode arrays

Contact Info

Product

Resources

About