Synaptic pathology in ALS-FTD

About the project

Dementia will affect 1 in 3 people in their lifetime. The inexorable decline in mental function, mood and movement ability comes about because of damage to synapses – the connections between nerve cells. Synapses come in many varieties and particular types are affected as dementia progresses. By finding and tracking these damaged synapses we can understand how the brain is damaged in dementia and help to bring on improvements in the diagnosis and treatment of these diseases.

We have recently developed ground-breaking technology that enables us to examine billions of individual synapses in the human brain and discover how the are damaged. We will now drive this technology forward to discover the synapses that are damaged in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS, or motor neuron disease, is a rapidly progressive, fatal condition which overlaps clinically, genetically and pathologically with frontotemporal dementia (FTD). ALS-FTD are the commonest forms of neurodegenerative disease in people under 65 years of age.

Our team of scientists from the UK and Japan will use several state-of-the-art microscopy methods to examine synapses in post-mortem brain tissue obtained from individuals who have had their behavioural features examined during life. This will potentially enable us to identify the synapses that when damaged cause speech and language impairments, deterioration in mood and emotions, and movement disorders.

The tools and knowledge from our program will inform on the use of brain imaging methods in the clinic and trials of therapies aimed at preventing the progression of ALS-FTD and other dementias. Our findings will also provide valuable data resources that can be exploited by the international scientific community to advance our understanding of the brain and its diseases.


Medical Research Council (MRC), Japan Agency for Medical Research and Development (AMED)


Curran, O. E., Qiu, Z., Smith, C., & Grant, S. G. N.
A single-synapse resolution survey of PSD95-positive synapses in twenty human brain regions.
Eur J Neurosci
2020 Jun 03
Zacco E, Kantelberg O, Milanetti E, Armaos A, Panei FP, Gregory J, Jeacock K, Clarke DJ, Chandran S, Ruocco G, Gustincich S, Horrocks MH, Pastore A, Tartaglia GG.
Probing TDP-43 condensation using an in silico designed aptamer.
Nat Commun. 2022 Jun 23;13(1):3306
2022 Jun 23

Primary location


Principal Investigator

Other people involved

Professor Colin Smith (Edinburgh University)

Dr Mathew Horrocks (Edinburgh University)

Professor Shigeo Okabe (Tokyo University)

Professor Akiyoshi Kakita (Niigata University)

Dr Jessica Griffiths (Edinburgh University)