Project acronym BRAINGAIN
Project NOVEL STRATEGIES FOR BRAIN REGENERATION
Researcher (PI) Andras Simon
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary In contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson’s disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.
Summary
In contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson’s disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym Neurogenesis
Project Exploration and promotion of neurogenesis in the adult brain
Researcher (PI) Jonas FRISÉN
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS3, ERC-2015-AdG
Summary It is now well established that new neurons are added to certain regions of the adult brain. There is today considerable interest in the development of regenerative therapies based on modulating endogenous neurogenesis, but it is necessary to better understand these events to assess whether this is rational and realistic.
This application takes its initiation in two recent discoveries that we have made: that astrocytes in the mouse striatum give rise to new neurons after stroke or inhibition of Notch signaling (Magnusson et al., Science, 2014) and that neurogenesis is a continuous process in the human striatum throughout adulthood (Ernst et al., Cell, 2014). We propose to characterize the molecular regulation of neurogenesis from striatal astrocytes in detail, and compare these astrocytes with those in other regions to understand why striatal astrocytes are uniquely neurogenic and whether astrocytes in other parts of the brain can be induced to give rise to new neurons. We will, moreover, assess the role of integration of new neurons in the striatal circuitry by inducing neurogenesis in the striatum in adult mice by blocking Notch signaling or by inducing stroke and modulate the activity of the new neurons by optogenetics and chemogenetics. We will, furthermore, study whether striatal neurogenesis is altered in human neurological diseases by retrospective birth dating by measuring the integration of 14C from nuclear bomb tests. We will assess whether inducing striatal neurogenesis in corresponding mouse models of neurological diseases has therapeutic potential.
This project will elucidate the molecular regulation of neurogenesis from astrocytes and the neurogenic potential of astrocytes in different parts of the brain, reveal the role of new neurons in the striatum, answer whether striatal neurogenesis is altered in common neurological conditions in humans and reveal whether inducing striatal neurogenesis may have therapeutic potential.
Summary
It is now well established that new neurons are added to certain regions of the adult brain. There is today considerable interest in the development of regenerative therapies based on modulating endogenous neurogenesis, but it is necessary to better understand these events to assess whether this is rational and realistic.
This application takes its initiation in two recent discoveries that we have made: that astrocytes in the mouse striatum give rise to new neurons after stroke or inhibition of Notch signaling (Magnusson et al., Science, 2014) and that neurogenesis is a continuous process in the human striatum throughout adulthood (Ernst et al., Cell, 2014). We propose to characterize the molecular regulation of neurogenesis from striatal astrocytes in detail, and compare these astrocytes with those in other regions to understand why striatal astrocytes are uniquely neurogenic and whether astrocytes in other parts of the brain can be induced to give rise to new neurons. We will, moreover, assess the role of integration of new neurons in the striatal circuitry by inducing neurogenesis in the striatum in adult mice by blocking Notch signaling or by inducing stroke and modulate the activity of the new neurons by optogenetics and chemogenetics. We will, furthermore, study whether striatal neurogenesis is altered in human neurological diseases by retrospective birth dating by measuring the integration of 14C from nuclear bomb tests. We will assess whether inducing striatal neurogenesis in corresponding mouse models of neurological diseases has therapeutic potential.
This project will elucidate the molecular regulation of neurogenesis from astrocytes and the neurogenic potential of astrocytes in different parts of the brain, reveal the role of new neurons in the striatum, answer whether striatal neurogenesis is altered in common neurological conditions in humans and reveal whether inducing striatal neurogenesis may have therapeutic potential.
Max ERC Funding
2 500 000 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
Project acronym QUALIAGE
Project Spatial protein quality control and its links to aging, proteotoxicity, and polarity
Researcher (PI) Lars Bertil Thomas Nyström
Host Institution (HI) GOETEBORGS UNIVERSITET
Call Details Advanced Grant (AdG), LS3, ERC-2010-AdG_20100317
Summary Propagation of a species requires periodic cell renewal to avoid clonal senescence. My
laboratory has described a new mechanism for such cell renewal in yeast, in which damaged
protein aggregates are transported out of the daughter buds along actin cables to preserve
youthfulness. Such spatial protein quality control (SQC) is a Sir2p-dependent process and by establishing the global genetic interaction network of SIR2, we identified the
polarisome as the machinery required for mitotic segregation and translocation of protein
aggregates. In addition, we found that the fusion of smaller aggregates into large inclusion
bodies, a process that has been suggested to reduce the toxicity of such aggregates, requires
actin cables and their nucleation at the septin ring. Sir2p controls damage segregation by
affecting deacetylation and the activity of the chaperonin CCT, enhancing actin folding and
polymerization. Considering that CCT has been implicated in mitigating
aggregation/toxicity of polyglutamine proteins, e.g. huntingtin, and that actin cables is
affecting formation, fusion, and resolution of aggregates, we hypothesize that CCT
deacetylation may underlie Sirt1¿s (mammalian orthologues of Sir2p) documented beneficial
effects in several neurodegenerative disorders caused by proteotoxic aggregates. This project
is aimed at approaching this hypothesis and to elucidate, on a genome-wide scale, how the
cell tether, sort, fuse, and detoxify aggregates with the help of CCT, actin cables, and the
polarity machinery. This will be accomplished by combining the power of synthetic genetic
array analysis, high-content imaging, genome wide proximity ligand assays, and microfluidics.
Using such approaches, the project seeks to decipher the machineries of the spatial quality
control network as a means to identify new therapeutic targets that may retard or postpone
the development of age-related maladies, including neurodegenerative disorders.
Summary
Propagation of a species requires periodic cell renewal to avoid clonal senescence. My
laboratory has described a new mechanism for such cell renewal in yeast, in which damaged
protein aggregates are transported out of the daughter buds along actin cables to preserve
youthfulness. Such spatial protein quality control (SQC) is a Sir2p-dependent process and by establishing the global genetic interaction network of SIR2, we identified the
polarisome as the machinery required for mitotic segregation and translocation of protein
aggregates. In addition, we found that the fusion of smaller aggregates into large inclusion
bodies, a process that has been suggested to reduce the toxicity of such aggregates, requires
actin cables and their nucleation at the septin ring. Sir2p controls damage segregation by
affecting deacetylation and the activity of the chaperonin CCT, enhancing actin folding and
polymerization. Considering that CCT has been implicated in mitigating
aggregation/toxicity of polyglutamine proteins, e.g. huntingtin, and that actin cables is
affecting formation, fusion, and resolution of aggregates, we hypothesize that CCT
deacetylation may underlie Sirt1¿s (mammalian orthologues of Sir2p) documented beneficial
effects in several neurodegenerative disorders caused by proteotoxic aggregates. This project
is aimed at approaching this hypothesis and to elucidate, on a genome-wide scale, how the
cell tether, sort, fuse, and detoxify aggregates with the help of CCT, actin cables, and the
polarity machinery. This will be accomplished by combining the power of synthetic genetic
array analysis, high-content imaging, genome wide proximity ligand assays, and microfluidics.
Using such approaches, the project seeks to decipher the machineries of the spatial quality
control network as a means to identify new therapeutic targets that may retard or postpone
the development of age-related maladies, including neurodegenerative disorders.
Max ERC Funding
2 371 262 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym Triploid Block
Project Mechanisms of polyploidy-mediated postzygotic reproductive isolation
Researcher (PI) Claudia Köhler
Host Institution (HI) SVERIGES LANTBRUKSUNIVERSITET
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary Polyploidization is a widespread phenomenon among plants and is considered a major speciation mechanism. Before becoming evolutionary successful, newly formed polyploids often have to overcome fertility bottlenecks, because mating with partners of lower ploidy causes incompatibilities in the endosperm leading to the formation of mainly non-viable progeny. This reproductive barrier is called the triploid block. Nevertheless, the most frequent route to polyploid formation is probably through unreduced gametes, suggesting that the triploid block can be overcome. Recent work from our laboratory uncovered a genetic pathway leading to unreduced gamete formation at high frequency and revealed that the triploid block is mainly caused by malfunction of Polycomb group (PcG) proteins. PcG proteins are evolutionary conserved proteins, which assemble into multimeric complexes with chromatin-modifying enzymatic activity, implicating epigenetic regulatory mechanisms as an important element of speciation. Here, I propose to unravel the underlying molecular mechanism(s) of the triploid block by identifying the responsible genes causing endosperm failure upon deregulation and their mechanism of regulation in response to interploidy crosses. I also plan to investigate whether genes that contribute to the triploid block are as well responsible for establishing interspecies incompatibilities within the Arabidopsis genus. This project will combine genetics, genomics and epigenomics and will make extensive use of knowledge and tools that we have been established in my laboratory over the recent years, making it likely that the proposed objectives can be achieved. The results of this project will be of interest to a broad scientific community, including biologists with a strong interest in epigenetic mechanisms as well as ecologists interested to understand mechanisms of plant speciation.
Summary
Polyploidization is a widespread phenomenon among plants and is considered a major speciation mechanism. Before becoming evolutionary successful, newly formed polyploids often have to overcome fertility bottlenecks, because mating with partners of lower ploidy causes incompatibilities in the endosperm leading to the formation of mainly non-viable progeny. This reproductive barrier is called the triploid block. Nevertheless, the most frequent route to polyploid formation is probably through unreduced gametes, suggesting that the triploid block can be overcome. Recent work from our laboratory uncovered a genetic pathway leading to unreduced gamete formation at high frequency and revealed that the triploid block is mainly caused by malfunction of Polycomb group (PcG) proteins. PcG proteins are evolutionary conserved proteins, which assemble into multimeric complexes with chromatin-modifying enzymatic activity, implicating epigenetic regulatory mechanisms as an important element of speciation. Here, I propose to unravel the underlying molecular mechanism(s) of the triploid block by identifying the responsible genes causing endosperm failure upon deregulation and their mechanism of regulation in response to interploidy crosses. I also plan to investigate whether genes that contribute to the triploid block are as well responsible for establishing interspecies incompatibilities within the Arabidopsis genus. This project will combine genetics, genomics and epigenomics and will make extensive use of knowledge and tools that we have been established in my laboratory over the recent years, making it likely that the proposed objectives can be achieved. The results of this project will be of interest to a broad scientific community, including biologists with a strong interest in epigenetic mechanisms as well as ecologists interested to understand mechanisms of plant speciation.
Max ERC Funding
1 447 596 €
Duration
Start date: 2011-10-01, End date: 2016-09-30
