DemaNDs Seminar - Monday 9 June 2025 - Dr Jade Haw

DemaNDs Seminar - Monday 9 June 2025 - Dr Jade Hawksworth

The next DemaNDs Seminar will be on Monday 9 June 2025.  Dr Jade Hawksworth (Newcastle University) will present ‘Beyond proteopathy: lipid dyshomeostasis in Lewy body dementia’ (abstract below). 

Refreshments will be available in Scafell room (1.05, 1st Floor, Biomedical Research Building, CAV) from 12.00 and the seminar will commence at 12.30pm in the Great Gable meeting room (1.01). Zoom details are below, though we encourage everyone who can to join in person.

Abstract:   Lewy body dementia (LBD) is a relatively common form of dementia characterised by accumulations of the protein alpha-synuclein (αSyn) into intraneuronal deposits termed Lewy bodies. Sphingolipid dyshomeostasis has long been implicated in LBD as genes encoding sphingolipid catabolic enzymes are risk genes for LBD, and sphingolipids alter αSyn conformation and aggregation rate. However, it is not yet clear how changes in sphingolipid metabolism modulate αSyn deposition in LBD.

We profiled 120 lipids spanning the entire sphingolipid degradation pathway, from globoside to ceramide, using LC-MS/MS in the cingulate cortex and lateral temporal cortex in post-mortem tissue from LBD patients (N=20) and controls (N=20). We interrogated the relationship between sphingolipid dyshomeostasis and αSyn, amyloid-beta (Aβ) and tau pathology by correlating abundance of sphingolipids with pathological burden in post-mortem brain tissue through immunohistochemistry, and quantified soluble and insoluble αSyn through Western blot.  

After regression against age and sex, we identified a number of sphingolipid species were elevated, notably including many of those associated with LBD risk genes, such as hexosylceramides/hexosylsphingosines and sphingomyelins. Network analysis indicated these lipids are implicated in membrane dynamics, alterations in which have previously been shown to regulate the aggregation of αSyn. A number of sphingolipids were significantly correlated with αSyn pathological burden, including hexosylceramides and sphingomyelins. Consistent with previous studies in Alzheimer’s disease, the abundance of GM3 ganglioside was significantly correlated with Aβ levels.

These findings suggest, for the first time, that sphingolipid homeostasis is altered in LBD. Furthermore, LBD brains manifest changes to a number of sphingolipids associated with genetic risk of LBD and, in some cases, their abundance is correlated with the severity of αSyn pathology. Taken together, these findings suggest that sphingolipid dyshomeostasis is implicated in LBD, where it may be associated with αSyn pathology.

 

Join Zoom Meeting:

https://newcastleuniversity.zoom.us/j/87546334590

Meeting ID: 875 4633 4590

Passcode: 151625