A novel strategy to control protein misfolding diseases and aging: Molecular mechanisms of transcellular chaperone signalling
Lead Research Organisation:
University of Leeds
Department Name: Inst of Molecular & Cellular Biology
Abstract
An increasing number of individuals in our aging population is faced with the devastating
consequences of cumulative protein misfolding, one of the hallmarks leading to Alzheimer's or
Parkinson's Disease or ALS. In a multicellular setting, protein misfolding diseases use mechanisms to
promote and spread the disease across different tissues and organs. Recent findings have
established that within the context of an entire organism, protective cellular mechanisms are at place
that allow to communicate stress and disease conditions across different tissues. For example, using
C. elegans as a model system, we have shown that mild stress induced in one tissue leads to a cytoprotective
chaperone response in multiple different tissues, known as Transcellular Chaperone
Signalling (Cell. 2013; 153(6): 1366-78). This results in increased stress resistance, extends lifespan
and protects from protein misfolding in different cell types. Although transcellular chaperone signalling
is conserved, the key players and the molecular mechanism of this inter-tissue signalling remain
elusive thus far. Using genetic screens and transcriptome analysis, we have identified novel
components of the proteostasis network that play an instructive role in the activation of protective
stress responses across and between different tissues.
In this project we will focus on these newly identified components, that comprise of secreted peptides
involved in the immune response and a transcription factor that belongs to the conserved BTB-ZF
family. We will determine how they signal and activate protective responses in different tissues of C.
elegans. We will investigate how the BTB-ZF transcription factor is involved in the regulation of
proteostasis and which protective gene programmes are initiated during stress, disease and aging,
using tissue-specific chromatin profiling (ChIP-Seq) techniques in C. elegans.
Finally, we will determine how the newly identified components can be used for the development of
novel therapeutic interventions against human protein misfolding diseases. In particular we will
elucidate which of the novel components have the capacity to delay protein aggregation using C.
elegans models of human protein misfolding diseases, including Alzheimer's Disease and
Huntington's Disease.
consequences of cumulative protein misfolding, one of the hallmarks leading to Alzheimer's or
Parkinson's Disease or ALS. In a multicellular setting, protein misfolding diseases use mechanisms to
promote and spread the disease across different tissues and organs. Recent findings have
established that within the context of an entire organism, protective cellular mechanisms are at place
that allow to communicate stress and disease conditions across different tissues. For example, using
C. elegans as a model system, we have shown that mild stress induced in one tissue leads to a cytoprotective
chaperone response in multiple different tissues, known as Transcellular Chaperone
Signalling (Cell. 2013; 153(6): 1366-78). This results in increased stress resistance, extends lifespan
and protects from protein misfolding in different cell types. Although transcellular chaperone signalling
is conserved, the key players and the molecular mechanism of this inter-tissue signalling remain
elusive thus far. Using genetic screens and transcriptome analysis, we have identified novel
components of the proteostasis network that play an instructive role in the activation of protective
stress responses across and between different tissues.
In this project we will focus on these newly identified components, that comprise of secreted peptides
involved in the immune response and a transcription factor that belongs to the conserved BTB-ZF
family. We will determine how they signal and activate protective responses in different tissues of C.
elegans. We will investigate how the BTB-ZF transcription factor is involved in the regulation of
proteostasis and which protective gene programmes are initiated during stress, disease and aging,
using tissue-specific chromatin profiling (ChIP-Seq) techniques in C. elegans.
Finally, we will determine how the newly identified components can be used for the development of
novel therapeutic interventions against human protein misfolding diseases. In particular we will
elucidate which of the novel components have the capacity to delay protein aggregation using C.
elegans models of human protein misfolding diseases, including Alzheimer's Disease and
Huntington's Disease.
Organisations
Publications
Miles J
(2020)
Tissue-Specific RNAi Tools to Identify Components for Systemic Stress Signaling.
in Journal of visualized experiments : JoVE
Miles J
(2019)
Expanding the Organismal Proteostasis Network: Linking Systemic Stress Signaling with the Innate Immune Response
in Trends in Biochemical Sciences
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013840/1 | 30/09/2016 | 29/09/2025 | |||
1789864 | Studentship | MR/N013840/1 | 30/09/2016 | 30/03/2020 | Jay Miles |
Description | MRC Flexible Supplement Grant |
Amount | £800 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2017 |
End | 11/2017 |
Description | Post-thesis submission transition award |
Amount | £3,752 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2020 |
End | 06/2020 |
Description | Pint of Science Leeds 2018 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Pint of Science is an annual international event, in which researchers across numerous locations arrange multiple events in local/regional venues to communicate current research to the general public. The aim is to promote interest in many areas of research, and inform people as to what kind of research is currently being undertaken. |
Year(s) Of Engagement Activity | 2018 |
URL | https://pintofscience.co.uk/ |