Newton001 SLEEP DEPRIVATION IN PARKINSON'S DISEASE: BRAZIL AND UNITED KINGDOM RESEARCH NETWORK
Lead Research Organisation:
University of Surrey
Department Name: Biochemistry & Physiology
Abstract
The project aims to address the important topic of sleep disturbances in Parkinson's disease (PD) which is a growing health issue in Brazil, since life expectancy is significantly increasing across the decades (1970: 58.9 years; 1980: 62.8 years; 1990: 66.6 years; 2011: 74.3 years - World Health Rankings) and PD affects 1-3% of people over 65 years. Prevalence of neurodegenerative diseases is increasing in developing countries, in Brazil this is estimated to be 5.3%. In addition, economic development is associated with increased urbanization and shift work, which negatively impacts on sleep quality, generating several health problems (e.g. obesity, higher incidence of cancer, cardiovascular and metabolic disturbances) and increasing demand on the public health system. This project thus aims to address a strategic health problem in Brazil and will create a scientific Brazil-UK network to study the basic mechanisms underlying PD with novel, state-of-the-art analytical tools and approaches.
The overall aim of the project is to investigate the behavioural, neurochemical and metabolic changes following sleep restriction in an animal model of PD. We hypothesise that sleep deprivation will produce cognitive deficits, neurochemical and metabolic disruption. The behavioural and neurochemical experiments will be undertaken in the Neurophysiology Laboratory (Profs Lima and Louzada, Federal University of Paraná), a centre of excellence for the study of Parkinson's disease in Brazil. Samples will be analysed by targeted liquid chromatography/mass spectrometry (LC/MS) metabolomics (Prof Skene (University of Surrey). Additional added value will be provided by employing a second metabolomics platform, untargeted 1H NMR metabolomics to characterise brain, plasma and urine metabolite changes in the rat model (Dr Swann, University of Reading). The application of two complementary analytical approaches ensures wide metabolome coverage and using multiple sample types allows the metablic perturbations induced by sleep deprivation in PD to be studied at different levels.
The planned combination of behavioural, neurochemical and metabolomic approaches will enable a multi-faceted observation of circulating and central neuronal parameters that could identify possible molecular biomarkers of early neurodegeneration in PD with potential diagnostic value. There will also be a mutual exchange of researchers and postgraduate students between the UK and Brazil to share new ideas, techniques and approaches allowing mutual (global) growth. The results of the proposed experiments will advance understanding of the mechanisms of PD and its inter-relationship with sleep/wake processing. Creation of a Brazil-United Kingdom research network will also provide a foundation for future studies and collaboration.
The overall aim of the project is to investigate the behavioural, neurochemical and metabolic changes following sleep restriction in an animal model of PD. We hypothesise that sleep deprivation will produce cognitive deficits, neurochemical and metabolic disruption. The behavioural and neurochemical experiments will be undertaken in the Neurophysiology Laboratory (Profs Lima and Louzada, Federal University of Paraná), a centre of excellence for the study of Parkinson's disease in Brazil. Samples will be analysed by targeted liquid chromatography/mass spectrometry (LC/MS) metabolomics (Prof Skene (University of Surrey). Additional added value will be provided by employing a second metabolomics platform, untargeted 1H NMR metabolomics to characterise brain, plasma and urine metabolite changes in the rat model (Dr Swann, University of Reading). The application of two complementary analytical approaches ensures wide metabolome coverage and using multiple sample types allows the metablic perturbations induced by sleep deprivation in PD to be studied at different levels.
The planned combination of behavioural, neurochemical and metabolomic approaches will enable a multi-faceted observation of circulating and central neuronal parameters that could identify possible molecular biomarkers of early neurodegeneration in PD with potential diagnostic value. There will also be a mutual exchange of researchers and postgraduate students between the UK and Brazil to share new ideas, techniques and approaches allowing mutual (global) growth. The results of the proposed experiments will advance understanding of the mechanisms of PD and its inter-relationship with sleep/wake processing. Creation of a Brazil-United Kingdom research network will also provide a foundation for future studies and collaboration.
Technical Summary
Parkinson's disease (PD) is the second most common neurodegenerative disease, afflicting about 1% of people over 65 years and 4-5% of people over 85 years. The major clinical features include asymmetric onset of bradykinesia, rigidity, rest tremor and disturbances in balance. PD patients also experience prodromal, non-motor features, such as sleep disorders (insomnia, restless legs and periodic limb movements, rapid eye movement (REM) sleep behaviour disorder, excessive daytime sleepiness) and neuropsychiatric symptoms (depression, anxiety, apathy). Sleep disturbances and metabolic alterations may thus precede the cardinal motor features of PD by many years, and have been considered as early biomarkers of the premotor phase of PD. Accordingly, the overall aim of the present project is to investigate the behavioural, neurochemical and metabolic changes following chronic partial sleep deprivation in an animal model of PD. We hypothesise that sleep deprivation will produce cognitive deficits, neurochemical and metabolic disruption.
Control and PD rats will be sleep deprived by "gentle stimulation" made by tapping or gentle shaking of the cage whenever drowsiness or attempts to engage in a sleeping posture are observed (from 7:00 to 13:00 h daily, totally 6 h of sleep deprivation per day during 21 days). The animals will be kept undisturbed from 13:00-07:00 h, totally 18 h/day sleep recovery. Hence, this protocol is consistent with a chronic sleep restriction procedure that is similar to the sleep restriction experienced in our society today. Behavioural testing will be conducted in the open-field and object recognition tests for analysis of motor and cognitive parameters. Blood, urine and brain samples will be collected and analysed by capillary electrophoresis with laser-induced detection (LIF) (neurochemical analysis) and targeted liquid chromatography/mass spectrometry (LC/MS) and NMR metabolomics analysis.
Control and PD rats will be sleep deprived by "gentle stimulation" made by tapping or gentle shaking of the cage whenever drowsiness or attempts to engage in a sleeping posture are observed (from 7:00 to 13:00 h daily, totally 6 h of sleep deprivation per day during 21 days). The animals will be kept undisturbed from 13:00-07:00 h, totally 18 h/day sleep recovery. Hence, this protocol is consistent with a chronic sleep restriction procedure that is similar to the sleep restriction experienced in our society today. Behavioural testing will be conducted in the open-field and object recognition tests for analysis of motor and cognitive parameters. Blood, urine and brain samples will be collected and analysed by capillary electrophoresis with laser-induced detection (LIF) (neurochemical analysis) and targeted liquid chromatography/mass spectrometry (LC/MS) and NMR metabolomics analysis.
Planned Impact
N/A
Organisations
- University of Surrey, United Kingdom (Lead Research Organisation)
- University of Lleida, Spain (Collaboration)
- University of Padova (Collaboration)
- National Institute for Public Health and Environment (RIVM) (Collaboration)
- Imperial College London, United Kingdom (Collaboration)
- University of Helsinki, Finland (Collaboration)
- Federal University of Rio Grande do Norte (Collaboration)
- University of Milano-Bicocca (Collaboration)
- Federal University of Paraná (Collaboration)
Publications

Aurich MF
(2017)
Olfactory impairment is related to REM sleep deprivation in rotenone model of Parkinson's disease.
in Sleep science (Sao Paulo, Brazil)

Caspani G
(2019)
Gut microbial metabolites in depression: understanding the biochemical mechanisms.
in Microbial cell (Graz, Austria)

Caspani G
(2019)
Small talk: microbial metabolites involved in the signaling from microbiota to brain.
in Current opinion in pharmacology

Cavelli M
(2019)
Electrocortical high frequency activity and respiratory entrainment in 6-hydroxydopamine model of Parkinson's disease.
in Brain research

Cóppola-Segovia V
(2017)
ER Stress Induced by Tunicamycin Triggers a-Synuclein Oligomerization, Dopaminergic Neurons Death and Locomotor Impairment: a New Model of Parkinson's Disease.
in Molecular neurobiology

De La Iglesia HO
(2016)
Ancestral sleep.
in Current biology : CB

Diaz Heijtz R
(2019)
Editorial overview: CNS diseases and the microbiome.
in Current opinion in pharmacology

Diessler S
(2018)
A systems genetics resource and analysis of sleep regulation in the mouse.
in PLoS biology

Fagotti J
(2019)
Chronic sleep restriction in the rotenone Parkinson's disease model in rats reveals peripheral early-phase biomarkers.
in Scientific reports

Hughes ME
(2017)
Guidelines for Genome-Scale Analysis of Biological Rhythms.
in Journal of biological rhythms
Description | Our findings showed that sleep restriction in an animal model of Parkinson's disease altered several behavioural (reversal of locomotor activity impairment; cognitive impairment; delay of rest-activity rhythm) and metabolic parameters (branched-chain amino acids, tryptophan pathway, phenylalanine, and lipoproteins, pointing to mitochondrial impairment). If combined, our results reveal a plethora of parameters that represents reliable early-phase biomarkers of Parkinson's disease which can easily be measured and could be translated to human studies. |
Exploitation Route | Our findings in an animal model of Parkinson's disease revealed a panel of metabolite biomarkers that may signal early phase Parkinson's disease. These metabolites now need to be measured in human studies. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | Genone scale analysis guidelines |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | The published guidelines is a multi-author paper and will act as a blue print for large scale omics analysis of time-series data. |
Description | Sleep and Circadian Biomarkers |
Geographic Reach | Europe |
Policy Influence Type | Membership of a guideline committee |
Description | FAPESP - CONFAP - UK Academies |
Amount | R$ 35,000 (BRL) |
Funding ID | 2016/50417-3 |
Organisation | São Paulo Research Foundation (FAPESP) |
Sector | Public |
Country | Brazil |
Start | 05/2017 |
End | 04/2018 |
Description | MRC Newton001 |
Amount | £49,000 (GBP) |
Funding ID | MR/N006321/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2015 |
End | 10/2016 |
Title | Metabolomics in an animal model of Parkinson's disease |
Description | Combination of NMR and targeted LC-MS metabolomics approaches to provide broad coverage of the metabolome |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Using both NMR and targeted metabolomics approaches to investigate the effect of chronic sleep restriction in an animal mode of Parkinson's Disease (PD) has identified a broader range of metabolites involved. We propose that these metabolites may serve as reliable early-phase PD biomarkers which can easily be measured and could be translated to human studies. |
URL | https://www.ncbi.nlm.nih.gov/pubmed/30760786 |
Title | Metabolomics in PD |
Description | Database of metabolomics data from two analytical platforms (NMR and LC/MS) looking at the effect of chronic sleep restriction on an animal model of Parkinson's disease (PD) |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | No |
Impact | The research database will only be made available once these data are published. Once this has occurred the subsequent impact can be assessed. |
Description | Bile acids |
Organisation | Imperial College London |
Department | Imperial College Trust |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Our expertise in chronobiology and sleep, access to biological samples, data and facilities |
Collaborator Contribution | Access to their facilities and expertise in metabolomics and bile acid measurment |
Impact | Research collaboration and research grant |
Start Year | 2015 |
Description | Gut microbiota |
Organisation | Imperial College London |
Department | Department of Surgery and Cancer |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Metabolomics LC/MS dataset; expert knowledge of circadian rhythms |
Collaborator Contribution | Expertise in gut microbiota analysis; training of research staff |
Impact | Collaboration is multi-disciplinary (physiology/pharmacology; analytical chemistry). |
Start Year | 2018 |
Description | Model of Hyperammonemia |
Organisation | University of Helsinki |
Country | Finland |
Sector | Academic/University |
PI Contribution | Development of targeted LC/MS method to measure metabolites in rat brain tissue |
Collaborator Contribution | Designed and performed sleep deprivation experiments in a rat model of hyperammonemia; collected brain tissue samples |
Impact | Research publication and conference presentations |
Start Year | 2016 |
Description | Model of Hyperammonemia |
Organisation | University of Padova |
Country | Italy |
Sector | Academic/University |
PI Contribution | Development of targeted LC/MS method to measure metabolites in rat brain tissue |
Collaborator Contribution | Designed and performed sleep deprivation experiments in a rat model of hyperammonemia; collected brain tissue samples |
Impact | Research publication and conference presentations |
Start Year | 2016 |
Description | NMR and LC/MS metabolomics in Parkinsons disease |
Organisation | Federal University of Paraná |
Country | Brazil |
Sector | Academic/University |
PI Contribution | Our expertise in chronobiology and sleep, protocol design, LC/MS metabolomics and data sharing |
Collaborator Contribution | Imperial's expertise in NMR metabolomics; Federal University of Parana's expertise in animal model of Parkinson's disease; National Institute for Public Health and Environment (RIVM) expertise in statistical and data analysis |
Impact | Metabolomics data generation; Conference presentations; Grants and scholarship proposals; Collaboration is multi-disciplinary |
Start Year | 2015 |
Description | NMR and LC/MS metabolomics in Parkinsons disease |
Organisation | Imperial College London |
Department | Department of Surgery and Cancer |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Our expertise in chronobiology and sleep, protocol design, LC/MS metabolomics and data sharing |
Collaborator Contribution | Imperial's expertise in NMR metabolomics; Federal University of Parana's expertise in animal model of Parkinson's disease; National Institute for Public Health and Environment (RIVM) expertise in statistical and data analysis |
Impact | Metabolomics data generation; Conference presentations; Grants and scholarship proposals; Collaboration is multi-disciplinary |
Start Year | 2015 |
Description | NMR and LC/MS metabolomics in Parkinsons disease |
Organisation | National Institute for Public Health and Environment (RIVM) |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | Our expertise in chronobiology and sleep, protocol design, LC/MS metabolomics and data sharing |
Collaborator Contribution | Imperial's expertise in NMR metabolomics; Federal University of Parana's expertise in animal model of Parkinson's disease; National Institute for Public Health and Environment (RIVM) expertise in statistical and data analysis |
Impact | Metabolomics data generation; Conference presentations; Grants and scholarship proposals; Collaboration is multi-disciplinary |
Start Year | 2015 |
Description | Peripheral neuropathy metabolomics |
Organisation | University of Milano-Bicocca |
Country | Italy |
Sector | Academic/University |
PI Contribution | We will perform targeted LC/MS metabolomics on samples collected by our partners |
Collaborator Contribution | Our partners will perform experiments (effect of chemotherapy on peripheral neuropathy in an animal model) and collect samples for our analysis |
Impact | Experiments are ongoing. |
Start Year | 2018 |
Description | Sleep in rotenone model of Parkinson's disease |
Organisation | Federal University of Paraná |
Country | Brazil |
Sector | Academic/University |
PI Contribution | Offered initial support to establish a network of researchers |
Collaborator Contribution | Lima at UFPR has created a Network of researchers to facilitate funding opportunities and collaborative research |
Impact | Joint publications |
Start Year | 2017 |
Description | Sleep in rotenone model of Parkinson's disease |
Organisation | Federal University of Rio Grande do Norte |
Country | Brazil |
Sector | Academic/University |
PI Contribution | Offered initial support to establish a network of researchers |
Collaborator Contribution | Lima at UFPR has created a Network of researchers to facilitate funding opportunities and collaborative research |
Impact | Joint publications |
Start Year | 2017 |
Description | Sleep in rotenone model of Parkinson's disease |
Organisation | University of Lleida |
Country | Spain |
Sector | Academic/University |
PI Contribution | Offered initial support to establish a network of researchers |
Collaborator Contribution | Lima at UFPR has created a Network of researchers to facilitate funding opportunities and collaborative research |
Impact | Joint publications |
Start Year | 2017 |
Description | International Biomarkers Workshop |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Representatives from international Sleep and Circadian Rhythm Societies attended a day workshop (Boston, US) to discuss standardisation of methods to uncover sleep and circadian biomarkers. A white paper has been proposed. |
Year(s) Of Engagement Activity | 2017 |
Description | Lecture delivered at University College Cork, Ireland |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Delivered a talk at the University College Cork in Ireland 2020. The lecture was largely attended by principal investigators, post-doctoral researchers and PhD students. The lecture focused on our current understanding of gut microbial metabolism and how metabolites arising from this activity can impact on host health and disease. Discussions afterwards led to the emergence of several new collaborations between my research group and investigators based in Cork. This spanned potential projects relating to the gut-brain axis, exercise, muscle metabolism, classical microbiology. |
Year(s) Of Engagement Activity | 2020 |
Description | Milano-Bicocca Workshop |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Gave a talk at Neurobiology Workshop (University of Milan-Bicocca) emphasising the value of Metabolomics as a tool for neuroscience research. Developed a research collaboration with Prof Guido Cavaletti. We are actively seeking research funding. |
Year(s) Of Engagement Activity | 2017 |
Description | Mood, Mind and Microbes annual meeting Amsterdam 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | An invited talk at the Mood, Mind and Microbes annual meeting in Amsterdam. The focus of my talk was the role of the microbiota in the gut-brain axis including in disease states such as Parkinson's. The audience was made up of academic researchers, post-graduate students, industry representatives from food and pharmaceutical companies as well as writers/journalists. A promotional video was created from the conference and I gave an interview that is now publicly available about the gut-brain axis. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.mindmoodmicrobes.org |
Description | Pint of Science - Human Brain? Microbial Mind? |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | This was a national outreach activity (Pint of Science) intended to educate the general public about novel areas of research occurring in the UK. It was designed to be an informal 15 minute talk delivered in a pub with minimal scientific jargon. Several questions were asked after the talk about how to improve the health of the intestinal microbiota through the diet. |
Year(s) Of Engagement Activity | 2019 |
URL | https://pintofscience.co.uk/ |