Studies on human tissue

Parkinson’s disease (PD) is a debilitating and progressive neurodegenerative disease for which there is currently no cure. In the brain, PD is characterised by the accumulation of the protein alpha-synuclein into characteristic neuronal inclusions called Lewy bodies. By electron microscopy, Lewy bodies are shown to be composed of aSyn fibrils radially arranged around an electron dense core. It is not known what causes the formation of a Lewy body, but it is thought that under disease conditions aSyn misfolds and oligomerises into fibrils which then accumulate in the cell to form the distinct round Lewy bodies. However, Lewy bodies only represent a small proportion of aSyn pathology in the brain of PD patients, and we recently showed that there was an abundance of aSyn pathology in human brain that is composed of mixed membrane fragments, vesicles and dystrophic cellular organelles, instead of the expected fibrillar inclusions.

In similar fashion, related diseases, such as Multiple Systems Atrophy, Dementia with Lewy Bodies, Alzheimer's disease, and Amytrophic Lateral Sclerosis, share similar characteristics in the post-mortem brain tissue. We aim to further investigate the ultrastructure of these fibril rich inclusions in various different diseases.


In order to design treatments that are effective in modifying the disease, it is imperative to ascertain what the mechanism is behind the formation of aSyn pathology in PD (or the respective proteinopathy in the respective disease), and whether it is driven by fibril accumulation, protein-membrane interactions or both. As there is currently no animal model which can faithfully recreate human neurodegenerative pathology, mechanistic information must come from post-mortem human brain.    

Our projects utilise our newly developed room-temperature CLEM pipeline to investigate the ultrastructure of the diverse spectrum of aSyn, Tau, Amyloid Beta and TDP-43 pathology seen in the post-mortem human brain of brain donors. By characterising the molecular components and corresponding 3D ultrastructures for the different pathological phenotypes of protein accumulation we hope to gain a deeper understanding of the driving forces behind disease progression.

Parkinson's Disease+-

Lewy Bodies are the central hallmark for Parkinson's Disease in the post-mortem human brain and we use CLEM to understand the temporal development of Lewy body formation. The main protein of interest is alpha-synuclein which can be found in fibrilar form in tissue inclusions in the human brain.

Multiple System Atrophy+-

Multiple System Atrophy (MSA) is another form of a synucleinopathy, sharing the fibrilar assembly of alpha-synuclein, like in PD. In this rapid progressing disease the inclusions can mainly be found in Glial Cytoplasmic Inclusions.

Dementia with Lewy bodies+-

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Alzheimer's disease+-

Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting tens of millions of people worldwide. Despite major efforts there is to date no cure for AD. Two major neuropathological hallmarks of AD are the aggregation of the proteins amyloid beta (Aβ) into plaques and hyperphosphorylated tau into neurofibrillary tangles (NFTs), which were shown to be cytotoxic. However, their formation and how they interact with their environment remains elusive.

Frontotemporal dementia+-

Frontotemporal dementias are the main dementia after Alzheimer's disease (AD) and are defined as early-onset dementia. They are characterized by an atrophy of the anterior temporal and frontal lobes. There is a wide range of clinical symptoms associated with FTDs, such as dementia, but also behavioural changes, such as character modification (lack of empathy and disinhibition), lack of executive abilities (attention, abstraction, planning, etc.), and motor impairment. They can be driven by tau-pathology, TDP-43 pathology or, in some cases, FUS-pathology. There are currently no cure nor any disease modifying therapy existing. (for more see Snowden 2023)

Amyotrophic Lateral Sclerosis+-

Amyotrophic Lateral Sclerosis, also known as Lou Gehrig and Jean-Marie Charcot disease, is the most prevalent motor neuron disease. ALS has an adult-onset and a life expectancy of 2 to 3 years after symptom onset. It can be driven by TDP-43, SOD1, c9orf72 or FUS mutation, but more than 30 other genes have been recognized as causative or risk factors in the disease onset. There are currently three FDA approved disease modifying therapies, however they only have a mild effect on lifespan. (for more see Mead et al., 2023 and Renton et al., 2014)