Genetic Insights into Neurodegenerative Diseases

Proteinopathies are diseases that are related to aging and involve the build-up of specific proteins in the brain. These proteins cluster together and create harmful structures in different types of cells. Certain neurodegenerative diseases can be linked to the same protein forming these clusters. For instance, a protein called alpha-synuclein (ɑS) can lead to the formation of Lewy bodies (LBs) and other aggregates, which are seen in conditions such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Many patients often show signs of multiple types of these diseases at once, complicating the situation further.

For example, a large percentage of Alzheimer’s disease (AD) patients also show signs of Lewy bodies. In fact, more than half of AD cases exhibit these structures, and the usual signs of AD, such as amyloid plaques and tau tangles, can also be found in DLB and even in a notable number of PD cases. This creates a complex picture and raises important questions: Do these diseases share a common biological cause? And are there shared risk factors across these protein-related diseases?

#Genetic Insights into Synucleinopathies

Rare variations in the gene responsible for ɑS, called SNCA, suggest a common ground among diseases linked to this protein. In families with genetic forms of synucleinopathies, such as those caused by mutations or duplications in SNCA, different disease outcomes, from PD to PDD to DLB, can occur within a single family.

Two specific hereditary forms of synucleinopathy linked to point mutations or duplications at the SNCA gene show connections to the protein aggregates seen in PD and MSA. Emerging research supports this idea. For instance, people with mutations in the GBA1 gene, which plays a role in a different genetic pathway, face a higher risk for PD and DLB, and recent findings suggest links to MSA as well. At the level of brain cells, the various synucleinopathies may arise from different regions of the brain being more susceptible to ɑS-related damage.

Studies are showing that different forms of the protein can exist, and patients with identical mutations might still exhibit unique disease presentations due to other factors, such as environment or genetic background. This reinforces that multiple factors can contribute to the distinct characteristics of these conditions.

#The Complexity of Mixed Pathologies

The presence of various protein types in the brain of patients with neurodegenerative diseases may point to overlapping disease processes or a shared underlying connection among different protein-related conditions. However, the connection might depend on clear signs of protein clusters being present.

Various studies looking into these diseases have generated mixed results. Nonetheless, a pattern is emerging that shows genetic overlaps among neurodegenerative conditions, including synucleinopathies. For example, variations in the MAPT gene, known for its relation to tau-related diseases, can also be linked to PD and DLB, while other genes like APOE and TMEM175 reveal shared risks between AD and DLB.

Interestingly, the presence of abnormal protein forms can lead to increased toxicity and aggregation, suggesting interactions between ɑS, Aβ, and tau proteins might be contributing to the overall disease processes. Research into the links between these proteins is ongoing, and while the lab studies offer promising leads, how these findings translate into real human contexts remains a question.

#Two Approaches to Understanding Neurodegenerative Diseases

Researchers are using two main genetic methods to unravel the complex workings of neurodegenerative diseases: human genetic analysis and studies involving model organisms. The most thorough studies to date on genetic modifiers have been done using yeast. There, researchers assessed how the presence of ɑS and Aβ proteins affects cell health. By analyzing almost the complete yeast genome alongside their corresponding proteins, they were able to identify ways in which specific genes might influence the toxicity caused by these proteins.

This yeast model is considered relevant to human disease as the genes identified are also connected to known factors in AD and PD. Despite these insights, little link exists between the effects seen in the yeast model with the effects seen with ɑS and Aβ in human studies.

In human genetics, genome-wide association studies (GWAS) have been the standard method used to find common variants related to diseases. These studies are typically focused on variants that are common in populations, but such variants usually possess minor effects, making it hard to pinpoint their roles. To target rare variants effectively, larger cohorts are needed. Recent studies have tried to narrow the search for these rare variants by focusing on specific types of genetic changes or particular functions.

In our work, we aimed to see if common links could be drawn between the modifiers of ɑS and Aβ in relation to their roles in AD and PD risk. We did targeted exome screening of genes connected to these proteins and also in known risk genes across a group of 496 patients diagnosed with different synucleinopathies.

#Findings from Genetic Screens

Our targeted genetic screenings showed significant enrichment of rare nonsynonymous variants in genes associated with known risks for PD, such as GBA1 and LRRK2. Notably, three known AD-associated genes also emerged, enhancing the understanding of shared risks between these diseases. After validation in independent datasets, a strong association emerged particularly for Aβ modifiers compared to ɑS modifiers.

This group of genes, along with PSEN2, revealed connections to the regulation of the Actin Cytoskeleton. It appears that a disruption of this framework within neurons is an important factor in both diseases.

PSEN2 was identified as being essential for neuron survival, which aligns with our findings that showed how its downregulation led to increased levels of SNCA. This points to a potential mechanism where mutations or deficiencies in PSEN2 might affect the onset of synucleinopathies by altering the expression of ɑS.

#The Role of the Actin Cytoskeleton

The actin cytoskeleton, which provides structure to cells and plays a key role in their function, emerged as a focal point among many genes related to PD and AD. Disruptions to this structure in neurons can lead to a cascade of negative effects, including impaired cellular functions and increased neurotoxicity linked with protein aggregates.

Our findings emphasize that the PSEN2 and actin regulator genes align well with the observed pathology in both PD and AD. In neurons where PSEN2 is downregulated, key markers associated with synucleinopathy also increased, signaling that these pathways are interconnected.

#Neuronal Models and Observations

To better understand these relationships, we developed new stem cell models that mimic synucleinopathy. These models allowed us to examine how variations in ɑS expression lead to cellular changes over time. Initial observations showed that increased levels of ɑS lead to cellular damage and death, which reaffirms the link between this protein and neurodegenerative disease progress.

Interestingly, when the RhoA signaling pathway was reduced in these models, it led to a drop in actin stability and increased pathologic changes in ɑS. This supports the notion that disruptions in actin signaling may play a vital role in how neurodegenerative conditions develop.

#Implications for Understanding Disease Mechanisms

Research has shown that many neurodegenerative diseases don’t conform to traditional categories, as they often show mixed signs of various pathologies. This complexity suggests that a more tailored approach to categorizing these diseases based on the underlying biology, rather than simply focusing on clinical symptoms, may be beneficial in developing targeted therapies.

Our findings suggest that understanding the nuances of genetic variants associated with specific proteinopathies can help to reveal new pathways common to multiple diseases. Using this approach could lead to better identification of shared risk factors and ultimately improve therapeutic strategies.

#Conclusion

The intricate relationship between amyloid and tau proteins, the role of genetic factors, and how these can affect cellular structures like the actin cytoskeleton underlines the complexity of neurodegenerative diseases. As research continues to deepen our understanding, it becomes clearer that a more integrated view of neurodegenerative disorders can lead to better identification of targets for therapy.

By focusing on the genetic underpinnings of these diseases, as well as utilizing model systems to test these hypotheses, strides can be made toward understanding the interplay between different proteinopathies. The goal of this research is to pave the way for more effective interventions in managing or preventing these debilitating conditions.