Principal investigator: Dra. Carmen M. Fernández-Martos
The group of Neurometabolism (GMET)
There is increasing interest in the role of lifestyle factors in modifying the onset of neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and other types of dementia.
ALS is a devastating, irreversible neurodegenerative disease characterized by the progressive loss of motor neurons of brain and spinal cord. No cure is available to stop the natural neurodegenerative progression of ALS or to improve the lives of patients living with the disease. This devastating disorder represents one of the most challenging socio-economical problems of our future. Although the cause of ALS is not yet fully understood, numerous studies suggest that ALS may develop as a result of multiple complex factors, including metabolic alterations. A recently growing body of epidemiological evidence suggests that metabolic syndrome and its components (impaired glucose tolerance, obesity, hypertension, hypertriglyceridemia, hyperinsulinemia, cholesterol, ect) may be important in the development of ALS. Indeed, a recent epidemiological study has determined how leptin levels are inversely associated with ALS risk: increasing leptin concentrations were associated with longer survival of ALS patients, suggesting a possible link between leptin and the clinical features of ALS. Therefore, it is important to clearly identify links between metabolic factors (e.g. leptin) and the development of ALS. Lifestyle-related diseases are potentially preventable, and their incidence can be simply decreased with the development of social-educational strategies accompanied by changes in diet and promoting physical activity.
In this context, our research aims to objectively and rationally uncover the weaknesses of the knowledge about the value of leptin as a therapeutic to ALS. To achieve this goal, in the laboratory we employ highly relevant models of ALS pathology (hTDP-43A315T (Prnp-TARDBP*A315T)95Bal, TDP-43 bigenic mice (NEFH-hTDP-43ΔNLS) and TDP-43 knock-in mouse model of FTD (TDP-43Q331K/Q331K mice) in combine with multidisciplinary methods of biochemistry (biomarkers/plasma ELISA assays), molecular biology (mRNA-Seq and mRNA/protein arrays), flow cytometry techniques (FACS analysis and cell subset analysis) and behavioral memory (Y maze and new location recognition task (NLR)) and motor (Catwalk and rotarod test) test, utilizing different aspects from many areas such as Molecular Biology and Biochemistry, Pathophysiology and Endocrinology, and Neuroscience and Neural disorders.
-Yao Liu, Kelsey A. Hanson, Graeme McCormack, Justin Dittmann, James C. Vickers, Anna E. King and Carmen M. Fernandez-Martos. Enhanced anti-amyloid effect of combined leptin and pioglitazone in APP/PS1 transgenic mice. Journal of Alzheimer’s Disease (JAD). 2019 (Under review).
-A. E. King, Anna Brain, K. Hanson, J. Dittmann, J. C. Vickers, Carmen M. Fernandez-Martos*. Disruption of leptin signalling in a mouse model of Alzheimer's disease. Metabolic Brain Disease. 2018 Aug;33(4):1097-1110.
-Stuart KE, King AE, Fernandez-Martos CM, Summers MJ, Vickers JC. Midlife environmental enrichment increases synaptic density in CA1 in a mouse model of Aβ-associated pathology and positively influences synaptic and cognitive health in healthy ageing. J Comp Neurol. 2017. 525(8):1797-1810.
-Stuart KE, King AE, Fernandez-Martos CM, Dittmann J, Summers MJ, Vickers JC. Environmental novelty exacerbates stress hormones and Aβ pathology in an Alzheimer’s model. Sci Rep. 2017 Jun 5;7(1):2764.
-Kelsey Hanson, Carmen M. Fernandez-Martos, James C Vikers, Anna E. King. The role of microtubules in excitotoxin-induced axon degeneration. Alzheimer's and Dementia. 2017 July;13(7):P953.
-*Carmen M Fernandez-Martos, Rachel AK Atkinson, Meng I Chuah, Anna E King, James C Vickers. Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer's disease. Alzheimer's & Dementia (N Y).2016 Dec 20;3(1):92-106 (*Corresponding author).
-R. Atkinson, J. Leung, C. Fernandez-Martos, Julie Atkin, J. C. Vickers, A. King. The role of FTD/ALS associated protein, TDP-43, in neurite and synapse health and function. Journal of Neurochemistry. 2016 August, 138 (Suppl. 1), 222–428.
-JC Vickers, A Woodhouse, CM Fernandez-Martos, MT Kirkcaldie, AJ Canty, GH McCormack, AE King. Defining the earliest pathological changes of Alzheimer’s disease. Curr Alzheimer Res. 2016; 13(3):281-7.
-*Carmen M. Fernandez-Martos, Anna E. King, Rachel A.K. Atkinson, Adele Woodhouse, James C. Vickers. Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite and synaptic pathology in the APP/PS1 transgenic model of Alzheimer’s disease. Neurobiology of Aging. 2015. 36(10):2757-67 (*Corresponding author).
-R. Atkinson, C. Fernandez-Martos, J. C. Vickers, A. King. The role of FTLD-associated proteins in neurite and synapse health and function. Journal of Neurochemistry. 2015 August, 134 (Suppl. 1), 272–382.
-Atkinson RA, Fernandez-Martos CM, Atkin JD, Vickers JC, King AE. C9ORF72 cellular localization and expression over mouse development. Acta Neuropathologica Communications. 2015. 3(1):59.
(2016) AU2016902618: Combinational Therapy for AD. Inventors: C.M. Fernandez-Martos, J. Vickers &A. King. University of Tasmania, Australia.
(2013) ES2395370: Use of ObRb agonist receptor as a novel therapeutic treatment of CNS injury and Neuropatic Pain.Inventors: C.M. Fernandez-Martos & F.J. Rodriguez. National Hospital for Paraplegics (FUHNPAIIN), Spain.
Carmen M. Fernández-Martos: Principal investigator.
Águeda Ferrer Donato: Pathology-Cytology lab technician.
Marta Cabrera Pinto: Pathology-Cytology lab technician.
Major ongoing collaborations
1. Prof. James Vickers. Chair of Pathology at the University of Tasmania, co-Director of the Wicking Dementia Research and Education Centre and Deputy Dean of the Faculty of Health, University of Tasmania (Australia). Topic: Neurodegenerative diseases (Alzheimer's disease), traumatic brain injury, structural brain plasticity, ageing-related changes in cognition and health services for dementia.
2. A/Prof. Anna King. Wicking Dementia Research and Education Centre. University of Tasmania (Australia). Topic: Alzheimer's disease, Frontotemporal dementia and Amyotrophic lateral sclerosis.
3. Dr Jemeen Sreedharan. Research Maurice Wohl Clinical Neuroscience Institute. King’s College London (UK). Topic: Frontotemporal dementia and Amyotrophic lateral sclerosis.
4. Prof. Nuria Del Olmo. Department of Pharmaceutical and Food Sciences. FUSP-CEU, Madrid (Spain). Topic: Synaptic plasticity.
5. Dr Adam Walker. Ross Maclean Fellow. Queensland Brain Institute (Australia). Topic: Motor neuron disease (MND)/amyotrophic lateral sclerosis (ALS). Molecular mechanisms of disease and pre-clinical studies in model systems.
6. Dr. Julie Chowen. Department of Endocrinology at the Hospital Infantil Universitario Niño Jesús in Madrid (Spain). Topic: Neuroendocrinology, sexual dimorphism, obesity and metabolism.
7. Prof. Susana Seseña Prieto. University of Castilla-La Mancha (UCLM). Topic: Food microbiology.
8. Prof. Ana Maria Rodriguez Cervantes. University of Castilla-La Mancha (UCLM). Topic: Atmospheric Chemistry and Air Pollution research.
- Understanding disease mechanism in ALS.
- Non-pharmacological approaches in ALS.
- Pharmacological approaches in ALS.
- Environmental risk factors in ALS.
-Ongoing Research Support related to the topic
1. Linking TDP-43 pathology and leptin to Amyotrophic Lateral Sclerosis (ALS): Implications of metabolic alterations in the pathogenesis and treatment. Funded by: Consejería de Educación, Cultura y Deportes de Castilla-La Mancha (JCCM), Spain. Total amount: 115,500€. Start/End date: 01/01/2019 – 31/12/2021. Role: Principal investigator (PI).
2. A potential metabolic-targeted therapeutic for Amyotrophic lateral sclerosis (ALS): Leptin. Funded by: “La Caixa" and Fundación Francisco Luzón. Total amount: 500,000€. Start/End date: 15/10/2019 – 15/12/2022. Role: PI & Project coordinator.
3. “El potencial de la leptina como tratamiento para la ELA”. Burbutrices & Fundacion Solis. Total amount: 12,000€. Start/End date: 15/10/2018 –. Role: PI.
-Completed Research Support related to the topic
1. Axon protection in Alzheimer's disease. The Judith Jane Mason & Harold Stannett Williams Memorial, Australia. Total amount: 59,097€. Start/End date: 31/03/2015 - 31/03/2016. Role: Co-PI
2. Leptin and Pioglitazone: a new potential therapeutic intervention for Alzheimer disease (AD). Early Career Researcher grants (ECRG). University of Tasmania (Australia). Total amount: 5000€. Start/End date: 10/09/2014 - 31/12/2014. Role: PI
3. Characterization of the physiological effect of neurofilament light subunit (NFL) protein deficiency in Alzheimer’s disease pathology: a new therapeutic target for neurodegenerative disease. Research Enhancement grants (REGS). University of Tasmania (Australia). Total amount: 14,500€. Start/End date: 14/01/2014 - 31/12/2014. Role: PI