The GB Lab leads the first large-scale genetic study in Dementia with Lewy Bodies

Lewy Bodies

Dementia with Lewy bodies typical neuropathological findings. From Front Neurol. 2012 May 1;3:68. doi: 10.3389/fneur.2012.00068.

Our first large-scale project on Dementia with Lewy Bodies (DLB) was just published in the journal Human Molecular Genetics.

Here, together with a large consortium of researchers spread throughout the world, we have looked at all genetic areas that are known to be involved in Parkinson’s or Alzheimer’s disease and checked if they are also involved in DLB.
The reason to do this is based on the fact that DLB shares so many aspects with PD and/or AD (like shuffling gait and stiffness of movements for the first and dementia for the second), that it makes sense to see if the genetic factors that are relevant for the more common diseases are also involved in DLB.
Also, because there are so many similar characteristics between these diseases, sometimes it is difficult for a clinical diagnosis to be made correctly. Because of this, we tried to include only samples from individuals with a clinical diagnosis of DLB, but who had since died and their brain had been assessed by a neuropathologist to confirm the diagnosis. This means that our cohort is less likely to have mis-diagnosed cases (something that could bias the results).
When we looked at these genetic regions in DLB and compared them to the same regions from healthy individuals, we realised that some of them actually are associated with DLB.
The APOE region (APOE is the strongest genetic risk factor for AD) seems to also be strongly associated with DLB.
The gene encoding the alpha-synuclein protein is also associated with DLB. Alpha-synuclein had been show to be involved in conferring genetic risk to PD.
Lastly, a gene called SCARB2 is also associated with both DLB and PD. Not much is known about SCARB2 and its role in neurodegeneration, but what we do know is that it encodes a lysosomal protein. Lysosomes are responsible for clearing cellular waste, including unwanted proteins, so an association with the lysosome, in a disease characterised by increased deposition of proteins, is very exciting and has the potential to open novel roads into therapeutic approaches in the future.
But when we looked closer at these last two associations and compared them with what we knew from PD, we realised that although they are on the same genes, they are actually somewhat different. The association profile is different and this suggests that although the same genes are associated with both PD and DLB, the way in which they are involved in disease is different. It may be that the proteins they encode are more or less expressed in one disease and not another; it may be that this difference occurs only in some brain tissues; or something else – we’re not sure at the moment what these differences actually mean. What we do know is that our results clearly bring together these 3 common diseases, and they show that, from a mechanistic point of view, they are slightly different.
These are exciting results, which we are currently following up and expanding. Stay tuned for more.

For the news story written by the Parkinson’s UK, who partially funded the project, see here.

2 responses to “The GB Lab leads the first large-scale genetic study in Dementia with Lewy Bodies

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