“Synucleinopathies are age-dependent neurodegenerative diseases characterized by alpha-synuclein accumulation with distinct vulnerabilities across brain regions.”
Synucleinopathies are a group of age-related neurological disorders, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Most individuals are not diagnosed until these diseases have significantly progressed, as early symptoms, such as a reduced sense of smell, subtle cognitive or motor changes are too vague to serve as reliable indicators.
To uncover specific biological signs that appear earlier and clearly point to the disease process, researchers from Saarland University developed a study titled “Brain region-specific and systemic transcriptomic alterations in a human alpha-synuclein overexpressing rat model,” featured as the cover of Aging-US, Volume 17, Issue 10.
Understanding Synucleinopathies
Synucleinopathies are characterized by the abnormal buildup of the protein alpha-synuclein in the brain. When this protein misfolds, it accumulates inside neurons and forms toxic clumps that disrupt their normal function and threaten cell survival. Because brain samples from patients are usually obtained only after death, scientists rely on animal models to investigate how these diseases start and progress.
The Study: Exploring Early Gene Changes Associated with Synucleinopathies
A research team from Saarland University, led by Vivien Hoof and Thomas Hentrich, studied a genetically engineered rat model that overexpresses the human form of alpha-synuclein. Their goal was to examine how this protein affects gene activity in both the brain and the gut at different life stages.
The researchers focused on three brain regions known to be involved in movement and cognition: the striatum, cortex, and cerebellum. They examined gene expression in rats at two ages, at five and twelve months, representing early and mid-adulthood, roughly equivalent to young and middle-aged humans. Gut tissue was also studied to better understand the possible systemic effects of alpha-synuclein accumulation.
The Results: Early and Widespread Gene Changes Across the Brain and Gut
The study revealed that gene activity was more significantly disrupted in younger rats, particularly in the striatum, a key area for motor control. Many of the affected genes were involved in communication between nerve cells, suggesting that vital brain functions start shifting early in the disease process.
In older rats, changes were especially noticeable in the cortex and related to myelination, the process that insulates nerve fibers. Similar patterns have also been observed in patients with synucleinopathies, highlighting the value of the rat model.
Importantly, the team identified a core group of genes that were consistently altered across all three brain regions. Some of these same gene changes were also found in the gut, suggesting that the impact of alpha-synuclein accumulation is not limited to the brain but may influence the entire nervous system, including the enteric (gut) nervous system.
The Breakthrough: Evidence That Synucleinopathies May Begin Long Before Symptoms Appear
This study provides compelling evidence that synucleinopathy-related changes begin early at the molecular level, well before clinical symptoms emerge, challenging the notion that such diseases only manifest in later life. These early alterations are both brain region-specific and systemic. The presence of similar gene changes in the gut supports the growing understanding that synucleinopathies are not just brain disorders, but may affect the entire body. These early molecular signals could serve as biomarkers, helping to detect disease before lasting damage occurs.
The Impact: Opening New Paths for Early Detection and Intervention
These findings could shift research toward diagnosing synucleinopathies in their earliest stages. If similar patterns of gene activity can be identified in humans, potentially through blood or stool samples, it may be possible to detect these diseases years before symptoms arise. Early detection could enable timely and more effective treatment.
The study also sheds light on previously overlooked genes involved in neuroprotection and neural communication, which may become new targets for therapeutic development.
Future Perspectives and Conclusion
While synucleinopathies are often seen as diseases of aging, this study highlights that crucial biological changes may occur far earlier. Mapping these early molecular changes provides a strong foundation for developing new diagnostic tools and early-stage treatments. It also reinforces the need to study not just the brain but the entire nervous system, including the gut, which may serve as an accessible window into early disease processes.
Click here to read the full research paper published in Aging-US.
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