Retromer Recycling in Neuronal Plasticity Maintenance
Lead Research Organisation:
University of Cambridge
Department Name: Clinical Neurosciences
Abstract
CONTEXT
Brain plasticity is key to brain function, and an understanding of how plasticity mechanisms are maintained is key to understanding neurodegenerative conditions, such as Parkinson's (PD) and Alzheimer's (AD) diseases. Failure of plasticity mechanisms, with degeneration of neuronal structures, are some of the earliest features of neurodegeneration in both AD and PD.
We now have evidence that sheds new light on brain plasticity, with particular relevance to PD and AD. The molecule a1-chimaerin (a1-CHN) is known to constrain the morphological plasticity of dendritic spines, and our new data suggests that a1-CHN works via a complex of molecules known as retromer. This is an important insight, as it links retromer to synaptic plasticity, and retromer has previously been implicated in the causation of both PD and AD.
Our unpublished data suggests that a1-CHN promotes the internal storage of retromer-tagged membrane, in a store that may act as an 'internal reserve' for building and maintaining synapses. This suggests that CHNs have a dual role: they both constrain plasticity of spines, and also support synaptic growth indirectly, via a reserve store of synaptic proteins and membrane. This reserve is likely to be involved in the sorting and trafficking of important synapse proteins around the cell; it may therefore be crucial for the long-term stability of dynamic structures such as dendritic spines and axonal arbours.
Retromer has been pinpointed previously as one factor in the development of AD, in part due to its role in production of toxic A-beta peptide - which is increased when retromer levels fall too low. Moreover, recent evidence has shown that a genetic mutation in VPS35, one of the components of retromer, may also cause PD. This is part of an array of recent evidence suggesting that malfunctioning of trafficking mechanisms within the cell may underlie most forms of PD.
AIMS AND OBJECTIVES
During our studies we will examine the precise molecular mechanisms and regulation of the proposed CHN-retromer interaction.
- We will confirm the biological relevance of the complex.
- We will determine which other molecules are involved in the interaction.
- We will examine the molecular regulation of the trafficking mechanism.
APPLICATIONS AND BENEFITS
The CHN-retromer pathway we postulate is likely to be a fundamental mechanism that contributes to aspects of brain plasticity. Our work will therefore serve as a springboard for a broader range of studies examining how it contributes to different aspects of normal brain functioning.
More importantly, brain plasticity can fail in disease, and is required for repair after brain injury. Parkinson's and Alzheimer's are common neurodegenerative diseases that carry large socio-economic and health burdens. Published work has already suggested that retromer mechanisms may be a good target for tackling AD, and so the new light shed by our data may ultimately lead to better tailored strategies for both diseases.
Brain plasticity is key to brain function, and an understanding of how plasticity mechanisms are maintained is key to understanding neurodegenerative conditions, such as Parkinson's (PD) and Alzheimer's (AD) diseases. Failure of plasticity mechanisms, with degeneration of neuronal structures, are some of the earliest features of neurodegeneration in both AD and PD.
We now have evidence that sheds new light on brain plasticity, with particular relevance to PD and AD. The molecule a1-chimaerin (a1-CHN) is known to constrain the morphological plasticity of dendritic spines, and our new data suggests that a1-CHN works via a complex of molecules known as retromer. This is an important insight, as it links retromer to synaptic plasticity, and retromer has previously been implicated in the causation of both PD and AD.
Our unpublished data suggests that a1-CHN promotes the internal storage of retromer-tagged membrane, in a store that may act as an 'internal reserve' for building and maintaining synapses. This suggests that CHNs have a dual role: they both constrain plasticity of spines, and also support synaptic growth indirectly, via a reserve store of synaptic proteins and membrane. This reserve is likely to be involved in the sorting and trafficking of important synapse proteins around the cell; it may therefore be crucial for the long-term stability of dynamic structures such as dendritic spines and axonal arbours.
Retromer has been pinpointed previously as one factor in the development of AD, in part due to its role in production of toxic A-beta peptide - which is increased when retromer levels fall too low. Moreover, recent evidence has shown that a genetic mutation in VPS35, one of the components of retromer, may also cause PD. This is part of an array of recent evidence suggesting that malfunctioning of trafficking mechanisms within the cell may underlie most forms of PD.
AIMS AND OBJECTIVES
During our studies we will examine the precise molecular mechanisms and regulation of the proposed CHN-retromer interaction.
- We will confirm the biological relevance of the complex.
- We will determine which other molecules are involved in the interaction.
- We will examine the molecular regulation of the trafficking mechanism.
APPLICATIONS AND BENEFITS
The CHN-retromer pathway we postulate is likely to be a fundamental mechanism that contributes to aspects of brain plasticity. Our work will therefore serve as a springboard for a broader range of studies examining how it contributes to different aspects of normal brain functioning.
More importantly, brain plasticity can fail in disease, and is required for repair after brain injury. Parkinson's and Alzheimer's are common neurodegenerative diseases that carry large socio-economic and health burdens. Published work has already suggested that retromer mechanisms may be a good target for tackling AD, and so the new light shed by our data may ultimately lead to better tailored strategies for both diseases.
Technical Summary
Neurons of the central nervous system must maintain, over protracted periods, a careful balance between morphological stability and synaptic plasticity. Chimaerins (CHNs) are proteins that constrain neuronal morphology plasticity via inhibition of the GTPase Rac1. We have identified that CHNs may work in conjunction with the intracellular protein complex retromer, to support synaptic function.
Retromer regulates intracellular sorting of cell surface receptors, and is linked to the pathogenesis of both Parkinson's and Alzheimer's diseases. Our data suggest that a1-CHN drives accumulation of the retromer subunit VPS35 in an endosomal compartment, suggesting a link between CHN function and retromer-recycling of synaptic receptors.
We propose a model in which a CHN-retromer pathway both internalises active signalling membrane from cell surface, and recycles membrane back to synapses in association with synaptic receptors. By this twin functionality - pruning weak connections and consolidating relevant synapses - a CHN-retromer mechanism would embody the characteristic behaviour of a healthy learning network, and also support long term synaptic function.
We plan an exploration of the proposed interaction between a1-CHN and retromer, focusing on the molecules involved, and the functional consequences of the mechanism. Using cell culture, super-resolution microscopy and biochemical techniques, we will examine:
- The biological relevance of the complex, confirming that what we have documented in preliminary data is a real and relevant interaction.
- The molecular components of the putative CHN-retromer complex, including specific retromer components (VPS35, VPS26, VPS29) and sorting nexins.
- Any interaction of the complex with the actin polymerising WASH complex and the functional role of this interaction.
These studies will lay the foundations for a future wider examination of retromer involvement in neurodegenerative diseases.
Retromer regulates intracellular sorting of cell surface receptors, and is linked to the pathogenesis of both Parkinson's and Alzheimer's diseases. Our data suggest that a1-CHN drives accumulation of the retromer subunit VPS35 in an endosomal compartment, suggesting a link between CHN function and retromer-recycling of synaptic receptors.
We propose a model in which a CHN-retromer pathway both internalises active signalling membrane from cell surface, and recycles membrane back to synapses in association with synaptic receptors. By this twin functionality - pruning weak connections and consolidating relevant synapses - a CHN-retromer mechanism would embody the characteristic behaviour of a healthy learning network, and also support long term synaptic function.
We plan an exploration of the proposed interaction between a1-CHN and retromer, focusing on the molecules involved, and the functional consequences of the mechanism. Using cell culture, super-resolution microscopy and biochemical techniques, we will examine:
- The biological relevance of the complex, confirming that what we have documented in preliminary data is a real and relevant interaction.
- The molecular components of the putative CHN-retromer complex, including specific retromer components (VPS35, VPS26, VPS29) and sorting nexins.
- Any interaction of the complex with the actin polymerising WASH complex and the functional role of this interaction.
These studies will lay the foundations for a future wider examination of retromer involvement in neurodegenerative diseases.
Planned Impact
The beneficiaries of this project, and they ways they will benefit, are summarised below.
ACADEMIC: In the short term (3-5 yrs) the main users of the research outputs from this project will be other academic groups. Outside the neurodegeneration field, these include a diverse array of research groups covering neuroscience, cancer and developmental biology. The diversity derives from the fundamental nature of retromer pathways. The connections with the proposed research are outlined in the Academic Beneficiaries section, but research groups with such related interests are present in the wider Cambridge biosciences community.
Within the field of neurodegeneration, the work has indirect relevance to the fields of protein processing, mitochondrial function, neurogenetics and functional imaging. Of particular interest may be the role of CHN-retromer in spread of neurodegenerative pathology between cells, via retromer-mediated secretory routes, which is increasingly recognised as important for disease spread within the brain.
TRANSLATIONAL RESEARCH GROUPS AND INDUSTRY: In the medium term (5-10 yrs) we hope that the main impact of the new understanding will be an opening up of new therapeutic options in the neurodegeneration field, via manipulation of the CHN-retromer pathway. Early work here has already suggested that retromer-directed treatments may have therapeutic potential in AD, but our insight could allow improved therapy design. In the context of recent successes in novel gene and RNA silencing therapies, the prospect of translation to treatment is more tangible than ever, but this also underlines the importance of better understanding of both physiological and disease mechanisms.
Cambridge is fortunate to have strong links already in place for translational work, both for PD and AD. For AD, the Dementia Research Institute (DRI, G Mallucci), is pioneering translational work in this field. The DRI is closely allied with the neighbouring Alborada Drug Discovery Institute, and with Biopharmaceutical companies interested in collaborative work also on the CBC site.
PATIENT INTEREST GROUPS: the biggest potential gains for this research are in the form of novel therapies that modify disease in common neurodegenerative conditions like PD and AD. Current therapies have no consistent ability to modify disease course, and consequently quality of life for millions is detrimentally impacted despite symptomatic treatments like levodopa. New rationally-designed therapies, using molecular manipulation at the genetic/RNA level, need only slow disease by a modest degree to have a major quality of life benefit for thousands of affected patients.
POLICY MAKERS: policy makers are currently struggling to keep up with novel therapies, particularly from the point of view of health funding, but also from an ethical standpoint, aspects that are closely intertwined. The relevance of our work to policy makers will only exist if viable therapies follow, but this is the primary aim of our strategy.
WIDER PUBLIC: the potential societal cost savings of disease modification in AD and PD are huge. These are driven by the long duration of the diseases with accumulating disability, accumulating pharmacological costs and above all accumulating care costs. For PD, estimated costs (including medical and social care, informal care costs borne by families, and loss of earnings) for the families of a person with PD (PwP) have been calculated at £20k annually per PwP household in the UK. With 145,000 PwP in the UK, the societal cost is nearly £3 billion / yr. Even a modest slowing of disease progression would have a major beneficial impact on such care costs.
ACADEMIC: In the short term (3-5 yrs) the main users of the research outputs from this project will be other academic groups. Outside the neurodegeneration field, these include a diverse array of research groups covering neuroscience, cancer and developmental biology. The diversity derives from the fundamental nature of retromer pathways. The connections with the proposed research are outlined in the Academic Beneficiaries section, but research groups with such related interests are present in the wider Cambridge biosciences community.
Within the field of neurodegeneration, the work has indirect relevance to the fields of protein processing, mitochondrial function, neurogenetics and functional imaging. Of particular interest may be the role of CHN-retromer in spread of neurodegenerative pathology between cells, via retromer-mediated secretory routes, which is increasingly recognised as important for disease spread within the brain.
TRANSLATIONAL RESEARCH GROUPS AND INDUSTRY: In the medium term (5-10 yrs) we hope that the main impact of the new understanding will be an opening up of new therapeutic options in the neurodegeneration field, via manipulation of the CHN-retromer pathway. Early work here has already suggested that retromer-directed treatments may have therapeutic potential in AD, but our insight could allow improved therapy design. In the context of recent successes in novel gene and RNA silencing therapies, the prospect of translation to treatment is more tangible than ever, but this also underlines the importance of better understanding of both physiological and disease mechanisms.
Cambridge is fortunate to have strong links already in place for translational work, both for PD and AD. For AD, the Dementia Research Institute (DRI, G Mallucci), is pioneering translational work in this field. The DRI is closely allied with the neighbouring Alborada Drug Discovery Institute, and with Biopharmaceutical companies interested in collaborative work also on the CBC site.
PATIENT INTEREST GROUPS: the biggest potential gains for this research are in the form of novel therapies that modify disease in common neurodegenerative conditions like PD and AD. Current therapies have no consistent ability to modify disease course, and consequently quality of life for millions is detrimentally impacted despite symptomatic treatments like levodopa. New rationally-designed therapies, using molecular manipulation at the genetic/RNA level, need only slow disease by a modest degree to have a major quality of life benefit for thousands of affected patients.
POLICY MAKERS: policy makers are currently struggling to keep up with novel therapies, particularly from the point of view of health funding, but also from an ethical standpoint, aspects that are closely intertwined. The relevance of our work to policy makers will only exist if viable therapies follow, but this is the primary aim of our strategy.
WIDER PUBLIC: the potential societal cost savings of disease modification in AD and PD are huge. These are driven by the long duration of the diseases with accumulating disability, accumulating pharmacological costs and above all accumulating care costs. For PD, estimated costs (including medical and social care, informal care costs borne by families, and loss of earnings) for the families of a person with PD (PwP) have been calculated at £20k annually per PwP household in the UK. With 145,000 PwP in the UK, the societal cost is nearly £3 billion / yr. Even a modest slowing of disease progression would have a major beneficial impact on such care costs.