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The role of TDP-43 in frontotemporal dementia and amyotrophic lateral sclerosis

Project details

Dr Jobert Vargas
UCL Queen Square Institute of Neurology
Research area
Alzheimer’s disease and dementia
Motor neurone disease
Funding type
Awarded in
May 2023


The Brain Research UK Miriam Marks Research Fellowship scheme was established in 2020 in partnership with UCL Queen Square Institute of Neurology. The scheme is funded by the Miriam Marks Endowment Fund, which was established by the family of Mrs Miriam Marks in 1971 to support research into brain degeneration.

This award to Dr Jobert Vargas is one of two Fellowships awarded in 2023, and will support his research into the disease processes underlying two devastating neurodegenerative conditions - frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).

About Dr Jobert Vargas

Jobert came to UCL from the US in 2019, under a joint PhD Neuroscience programme run by UCL and the US National Institute of Health. Jobert's PhD research focused on how cells get rid of waste materials, such as toxic proteins or damaged mitochondria, that accumulate in brains of patients with neurodegenerative diseases. His PhD work contributed towards therapeutic strategies that aim to manipulate the brain's garbage disposal machinery as a potential treatment for various neurodegenerative disorders. He was awarded his PhD in 2021.

He has since worked as a Research Fellow in the lab of Professor Giampietro Schiavo at UCL, where he also collaborates closely with Professor Pietro Fratta's group. He has already generated important data, the foundations for this ongoing work. Professor Schiavo has noted his talent and creativity, as well as his collaborative approach, and his generosity in mentoring students and colleagues.

This Fellowship will support his continued professional development, providing access to the world-class facilities at UCL, as well as at the UK Dementia Research Institute and the Francis Crick Institute, with which Professor Schiavo and Professor Fratta are affiliated. He will have access to a wealth of multi-disciplinary collaborators carrying out complementary research in these first-rate research environments.

About frontotemporal dementia and amyotrophic lateral sclerosis

Frontotemporal dementia and amyotrophic lateral sclerosis are two distinct neurodegenerative conditions with very different clinical presentations, but they lie on a disease spectrum each characterised by the selective death of frontotemporal cortex and motor neurones respectively. They also share causative genetic mutations.

Frontotemporal dementia (FTD) is the most common form of dementia in the under 60s. Caused by damage to cells in the frontal and temporal lobes, the front and side parts of the brain, the initial symptoms are changes to personality and behaviour and/or difficulties with language. This contrasts with the early symptoms of older-onset forms of dementia, which typically manifest as problems with memory.

The only known risk factors for FTD are genetic. Around one third of people with FTD have inherited an abnormal gene from a parent. In families with this genetic form of the disease, children have a 50% chance of inheriting the gene from the affected parent and thus developing the disease themselves. There are no treatments that can delay the onset, or prevent the progression, of FTD in those affected.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neurone disease. It is a fatal, rapidly-progressing disease that attacks the nerves controlling important muscle activity such as gripping, walking, speaking, swallowing and breathing. As these nerves are attacked, messages gradually stop reaching the muscles. This initially leads to weaking and wasting and then, eventually, severe paralysis and breathing difficulties. There is no cure for ALS, it is always fatal, but some people live with it for many years.

Around 10% of cases of ALS are familial.

Understanding the role of TDP-43 in FTD and ALS

As described above, FTD and ALS are distinct diseases, with unique symptomatology but part of a recognised clinical, neuropathological, and genetic disease continuum. This interrelation was strengthened with the discovery that in both FTD and ALS, the protein TDP-43, normally found within the nucleus of brain cells, leaves the nucleus and forms aggregates in the body of the cell. The reasons for this mislocalisation during FTD and ALS are unclear. When TDP-43 leaves the nucleus, it renders the protein unable to function properly, but the consequences of this, in terms of how it causes FTD and ALS, are not fully understood.

During the Fellowship, Jobert is carrying out a detailed study of TDP-43, to understand what happens when it is dysregulated in disease, and how this leads to the death of motor neurons (ALS) or cortical neurons (FTD). Crucially, he wants to understand the selectivity of FTD and ALS pathology - why is it only motor neurons or cortical neurons that are vulnerable, and not the whole body? 

Ultimately, understanding the functions of TDP-43 will aid the design of therapies targeting pathways that can halt disease progression.


FTD and ALS are devastating diagnoses. Neither has any treatment that can prevent progression, and they cause immense suffering - not just for the patients themselves but also for carers and family members.

We desperately need advances in research and treatment to offer hope to those affected, now and in the future.

This work by Dr Vargas is helping to unravel the complex underlying disease processes, which we hope will enable the design of therapies targeting these processes, to restore TDP-43 function, as a means to cure FTD and ALS.

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