July 2019

17 July - Dr Sarah Marzi

 

Dysregulation of histone acetylation in Alzheimer’s disease

Dr Sarah MarziDr Sarah Marzi
Centre for Genomics and Child Health, Blizard Institute
Queen Mary University of London



Biography
Sarah Marzi studied mathematics and psychology at the University of Freiburg before completing a PhD in epigenetics at King’s College London.  Her research interests lie in epigenetics of human complex diseases, particularly those relating to brain and neuropsychiatric phenotypes, and she uses genome-wide genetic and epigenetic techniques as well as innovative bioinformatic and statistical approaches to investigate epigenetic dysregulation in disease. Sarah is currently a postdoctoral researcher in Vardhman Rakyan’s lab at Queen Mary University of London working on epigenetic responses to nutritional stressors and genetic variation in human ribosomal DNA.

Abstract
Recent studies have implicated a role for regulatory genomic variation in Alzheimer’s disease (AD) progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, few studies have systematically examined other types of regulatory genomic modifications in AD. This talk will focus on results from a recent genome-wide study of lysine H3K27 acetylation (H3K27ac) – a robust marker of active enhancers and promoters – in entorhinal cortex samples from AD cases and matched controls (Marzi et al., 2018. Nat Neurosci). 

In addition to widespread acetylomic variation associated with AD neuropathology, we identified differentially acetylated peaks in the vicinity of genes implicated in both tau and amyloid neuropathologies, as well as in genomic regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions and AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. This is the first study of variable H3K27ac yet undertaken for AD; in addition to identifying molecular pathways associated with AD neuropathology, it serves as a framework for quantitative genome-wide studies of this modification in complex disease. 

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Wednesday 17 July 2019
16:00 - 17:00

Location
E519 Burlington Danes, Hammersmith Campus 

22 July - Dr Nathan Skene


Genetic identification of cell types underlying brain disorders and cognitive traits

Dr Nathan SkeneDr Nathan Skene 
Safra-UK DRI Junior Research Fellow in Bioinformatics
Imperial College London


Biography
Nathan Skene did an undergraduate degree in Artificial Intelligence and Cybernetics at the University of Reading, followed by an MPhil in Computational Biology at Cambridge. His PhD was at the Sanger Institute working with Prof Seth Grant on the Genes2Cognition programme. During his PhD he worked on analysing the transcriptomic changes seen in a mice carrying a wide range of synaptic mutations. His interests lie in using human genetics to gain insight into the neurobiology of brain disorders and cognitive traits. He did his postdoc in the lab of Jens Hjerling-Leffler at the Karolinska Institutet, where he developed a series of method which made it possible to identify cell types underlying complex diseases using GWAS data. He recently moved to Imperial as an Edmund and Lily Safra Fellow.

Abstract
Using a cellular taxonomy of the brain from single-cell RNA sequencing we have evaluated whether disease associated genomic loci are linked to particular brain cell types. We find evidence that schizophrenia is best explained by independent associations with four cell types: medium spiny neurons, cortical neurogliaform cells, pyramidal neurons and glutamatergic cells of the superior colliculus. We find that other psychiatric and cognitive traits which show strong genetic correlations to schizophrenia due to shared cellular mechanisms. Depression and neuroticism are however found to have greater involvement of the dopaminergic and serotonergic cell types. Neurological disorders show clear differences with Alzheimers associated with microglia, Parkinsons with dopaminergic cells and oligodendrocytes, and Stroke with arterial smooth muscle cells. As no prior studies had implicated oligodendrocytes as being causally involved in Parkinsons, we further investigated cellular changes in post-mortem Parkinson’s brains: we found that changes in oligodendrocytes precedes dopaminergic neuron degeneration in the substantia nigra.

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Monday 22 July 2019
16:00 - 17:00

Location
E519 Burlington Danes, Hammersmith Campus 

 

24 July - Dr Silvia Bolognin


Stem cell-derived 3D in vitro cultures as a relevant model for Parkinson’s disease

Dr Silvia BologninDr Silvia Bolognin
Luxembourg Centre for Systems Biomedicine (LCSB)
University of Luxembourg



Biography
Dr. Silvia Bolognin is a research associate at the University of Luxembourg. She graduated in Pharmaceutical Chemistry and Technology and she received her Ph.D. in Tissue and Grafting Engineering at the University of Padua, Italy. She was a post-doc fellow at the Institute for Basic Research in Developmental Disabilities in Staten Island, NY in the lab of prof. Khalid Iqbal and at the University of Verona, Italy. She was also a co-founder and acted as CTO of a spin-off company from the University of Luxembourg. Dr. Bolognin has focused on the mechanisms that regulate abnormal protein alteration in Alzheimer´s and Parkinson´s disease and the use of stem cell technology for disease modelling.

Abstract
The identification of promising drug candidates against Parkinson’s disease (PD) is hampered by the lack of sufficiently representative in vitro models. Human induced pluripotent stem cells (iPSCs) represent a promising tool to fill this gap. We optimized the cultivation of PD patient-specific neurons, derived from patients carrying the LRRK2-G2019S mutation, in 3D microfluidics. 3D conditions elicited an intrinsic time dependent dopaminergic degeneration due to LRRK2-G2019S, which was not observed in standard 2D conditions. This was preceded by an altered mitochondrial morphology, and increased cell death in LRRK2-G2019S neurons compared to isogenic lines without using stressor agents. We further increased the complexity of the models by generating midbrain organoids. In LRRK2-G2019S midbrain organoids, a decreased expression of astrocytes was observed after 35 days of differentiation. This was accompanied by an altered transcriptomic profile as shown by single-cell RNA sequencing. Interestingly, the defective astrocyte differentiation and the dopaminergic degeneration contributed to the acquisition of a senescent phenotype in organoids carrying the LRRK2-G2019S mutation. This data supports the use of advanced in vitro models to recapitulate key pathological hallmarks of this neurodegenerative disorder.

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Wednesday 24 July 2019
15:00 - 16:00

Location
E519 Burlington Danes, Hammersmith Campus 

 

 

26 July - Dr Yu Ye


Maintaining cell homeostasis by proteasome re-organisation – reversing protein aggregation in dementia


Dr Yu YeDr Yu Ye
Sir Henry Wellcome Research Fellow in Biotechnology
University of Cambridge and Harvard University



Biography
Yu Ye completed his PhD at the MRC-LMB, studying how deubiquitinating enzymes of the ubiquitin-proteasome system (UPS) interacted with distinct ubiquitin signals. During this time, he uncovered a novel mechanism of regulating deubiquitinase activity through the conformation of ubiquitin chains. Several of these deubiquitinases have since been shown to regulate cell stress responses implicated in neurodegenerative disorders. Awarded with a Sir Henry Wellcome Fellowship for his postdoctoral research, he initiated and built up a collaboration between Harvard and Cambridge to develop his own research direction, focusing on reversing protein aggregation with the UPS. He conceptualised and directed research in this novel area, for which he also established a dedicated research infrastructure. This resulted in several senior-author studies describing how proteasomes actively restricted aggregate size in vitro and how proteasomes re-organised to target aggregates in cells. He is now excited to expand this novel area of research into understanding the role of proteasome function in dementia.

Abstract
Aggregation of misfolded proteins is a pathological process implicated in neurodegenerative disorders and dementia. While much research has focused on how aggregates are assembled, the reverse process of aggregate removal is not well-studied. Reducing cell stress by limiting toxic protein aggregates is an important area of research, opening up novel potential routes of therapeutic intervention. Using state-of-the-art super-resolution and light-sheet microscopy and cell biology approaches, I have developed a unique research direction to investigate how proteasomes maintain cell homeostasis by targeting aggregates at distinct localisations. I also built up a dedicated research infrastructure and methodological approaches to study proteasomes and protein aggregates in cells. My in vitro results and studies in cells demonstrated that proteasomes restricted aggregate size and reorganised upon cell stress, assembling into foci around aggregates in a cytoskeleton-dependent manner. I will now to expand my research into characterising the mechanisms underlying proteasome response during aggregate entry into neurons, and during aggregate formation inside neurons over time. Uncovering processes involved in aggregate clearance and how proteasome malfunction is implicated in neuronal stress and degeneration will provide a better understanding of neurodegenerative disorders and ultimately establish approaches to restrict and reverse dementia.

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Friday 26 July 2019
11:30 - 12:30

Location
E519 Burlington Danes, Hammersmith Campus 

 

29 July - Dr Raffaella Nativio

The epigenetic landscape of healthy aging and Alzheimer's disease

Dr Raffaella NativioDr Raffaella Nativio
Research Associate in Epigenetics
University of Pennsylvania

 

Abstract
Aging is the top risk factor for Alzheimer's disease (AD),although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We find that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes having distinctive functional roles. Furthermore, we discover an association between the genomic locations of significant H4K16ac changes with genetic variants (SNPs) identified in prior AD genome-wide association studies (GWAS) and with expression quantitative trait loci (eQTLs). Our results establish the basis for an epigenetic link between aging and AD

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Monday 29 July 2019
16:00 - 17:00

Location
E519 Burlington Danes, Hammersmith Campus