Mutations in two proteins, called alpha-synuclein and tau, cause brain cell loss in patients with neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. Some brain cells are more vulnerable to these proteins than others, but it was, until now, unclear whether this was due to the cell types’ intrinsic properties or because they produce more of these proteins. Now, the group of Patrik Verstreken (VIB-KU Leuven Center for Brain & Disease Research) found evidence that some brain cells are more susceptible to disease-causing alpha-synuclein and tau. By studying which genes are involved in this vulnerability, the researchers hope to identify potential targets for therapies to treat these diseases.
Patrik Verstreken: “Our research aids the understanding of the vulnerability and resilience of brain cells to neurodegenerative diseases like Alzheimer’s and Parkinson’s. This is crucial to be able to develop new therapies that can provide relief to the millions of patients and their families affected by these devastating conditions.”
Alpha-synuclein or tau proteins can form clumps inside brain cells, leading to cell death and symptoms such as abnormal movements or cognitive decline. These clumps, or aggregates, are hallmarks of several neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mutations in alpha-synuclein or tau can cause rare familial forms of these diseases, which affect specific areas of the brain and some cells more than others.
Alpha-synuclein and tau are produced by cells all throughout the brain, but it was unclear why certain types of brain cells were more vulnerable to damage caused by defects in these proteins. Their cell-specific harmfulness may arise due to their interaction with particular features of different brain cell types or simply because of their increased expression within the cells. Now, the lab of Patrik Verstreken (VIB-KU Leuven Center for Brain & Disease Research) found that alpha-synuclein and tau are present at similar levels in both vulnerable and resilient cells, but resilient cells have different genes turned on that help protect them from damage caused by these proteins.
These findings provide new insight into the mechanisms that underlie neurodegenerative diseases and may help to identify new ways to prevent or treat these conditions.
Patrik Verstreken (left) and Roman Praschberger (right)
Reasons for resilience
The scientists studied data from human brain datasets and used a technique called single-cell RNA sequencing to examine over 200 different types of nerve cells in fruit flies. They looked at which cellular environments react most to alpha-synuclein or tau toxicity and which genes were turned on in different kinds of brain cells. The data indicated that resilient brain cells express genes related to energy production and cellular organization differently, which may protect them from damage caused by alpha-synuclein or tau buildup.
Specifically, brain cells that can resist damage from alpha-synuclein and tau proteins are set apart from vulnerable ones by differences in how they produce energy through mitochondria, in the case of alpha-synuclein. In the case of tau, resilient and susceptible cells are distinguished in how they organize connections between neurons and maintain proper calcium levels inside their cells. The scientists tested several genes in these pathways in a fly model and found that many reduced the toxic effects of the tau protein. Future studies will be necessary to uncover how calcium and other vulnerability-resilience pathways modulate tau toxicity to find new neurodegeneration drug targets.
Roman Praschberger, first author of the study: “What excites me most is that we might be able to harness nature’s own secrets for potential new drug targets by studying the differences between resilient and vulnerable neurons in neurodegenerative diseases.”