This highly interdisciplinary study, led by Krishna Jayant, PhD, Leslie A Geddes Assistant Professor of Biomedical Engineering in collaboration with Jean-Christophe Rochet, PhD, Donna L. Krinicki Director of the Purdue Institute for Integrative Neuroscience and Professor of Molecular Pharmacy and Medicinal Chemistry, explores the role of alpha-synuclein (α-syn), a protein that forms toxic aggregates called Lewy bodies in the brains of individuals with synucleinopathies. Using a novel experimental model, the team, injected preformed α-syn fibrils into two critical regions of the mouse brain: the dorsal striatum and the motor cortex. Both regions are known to be affected by the spread of α-syn pathology, but the study aimed to discern how these distinct areas influence the progression of the disease and crucially, its early neurophysiological markers.

Distinct Early Cortical Dysfunction Unveiled

What the team discovered was a profound difference in the patterns of cortical dysfunction triggered by the two seeding sites, offering an unprecedented window into possible cortical biomarkers the earliest stages of the disease.

“Our study suggests that Cortical dysfunction, possibly through pathology propagation across vulnerable pathways could serve as markers of early-stage progression of neurodegenerative diseases. By identifying electrophysiological biomarkers (e.g., abnormal brainwave patterns like beta-band dysfunction) and circuit features such as spatiotemporal organization of cellular activity, we believe we can detect disease much earlier than relying on traditional diagnostic methods such as imaging or postmortem analysis,” said Jayant.

Electrophysiological analysis revealed that both the striatal and cortical seeding sites led to increased cortical pathology and hyperexcitability. However, the team observed that the dynamics of this dysfunction were strikingly location-dependent. The motor cortex exhibited a unique progression of beta-band spike-field coherence—a critical marker of neural communication—starting in Layer 5 and gradually spreading to Layer 2/3 of the cortex.

"While the spreading of cortical hyperexcitability was seen in both seeding locations, the nature of the dysfunction was entirely different," said Hammad Khan, first author of the study and current NSF GRFP in the Weldon School of Biomedical Engineering. "The rate of entrainment and the tendency for beta burst dynamics to occur were markedly different for different α-syn fibril seeding locations and this effect could significantly influence the disease's trajectory."

Layer-5 Vulnerabilities and Beta Dysfunction

One of the most exciting aspects of the study the team discovered was the connection between Layer-5 dendritic vulnerabilities and the observed beta event dysfunction. These findings suggest that Layer-5 neurons—a critical layer in motor control—may be particularly susceptible to early-stage synucleinopathy-induced changes and a critical driver of aberrant beta dynamics in the cortex.

“We theorized that this Layer-5 induced effect on beta could further be leveraged as potential biomarkers for distinguishing between symptomatically similar synucleinopathies”, said Khan.

Implications for Early Diagnosis and Treatment

The identification of beta-band dysfunction as a specific marker of cortical involvement in synucleinopathies holds significant promise for the development of early diagnostic tools. While current diagnostic methods primarily rely on detecting physical markers such as Lewy bodies post-mortem, this study suggests that a combination of electrophysiological patterns could be used to detect the disorder in its early, prodromal phase.

What This Means for Synucleinopathies

Synucleinopathies—disorders caused by the misfolding and aggregation of α-synuclein—are notoriously difficult to diagnose early. Parkinson's disease, for instance, is often diagnosed only after significant motor symptoms have already appeared, leaving little opportunity for early intervention.

This new research offers a tantalizing glimpse of a future where electrophysiological biomarkers can provide early clues to the onset of these diseases, even when clinical symptoms are not yet apparent. Such insights could lead to earlier, more effective treatments, as well as tailored therapies that address the distinct disease trajectories seen in different synucleinopathies.

Looking Ahead

While the study’s findings are groundbreaking, much work remains to be done. Future studies will need to investigate whether similar patterns of dysfunction occur in humans, as well as the mechanisms behind the location-specific progression of α-syn pathology. The researchers also plan to explore potential therapeutic interventions aimed at stabilizing beta oscillations or protecting Layer-5 neurons from early damage.

"By continuing to study the circuit signatures of synucleinopathies, we hope to create a clearer roadmap for early intervention," Rochet, an expert in synucleinopathies and senior author on the study concluded. "This could dramatically change how we approach these diseases, which have long been among the most challenging to treat."

With the promise of early detection and more precise treatments, this study marks an exciting step forward in the battle against neurodegenerative diseases and offers hope for millions living with synucleinopathies worldwide.

Using the scientific findings in this study, the Jayant group is creating technologies for early stage biomarker detection and therapuetic intervention. 

Jayant disclosed his innovation to the Purdue Innovates Office of Technology Commercialization, which has applied for a patent from the U.S. Patent and Trademark Office to protect the intellectual property. Industry partners interested in developing or commercializing the innovation should contact otcip@prf.org and refer to track code 70990.

About Purdue Innovates Office of Technology Commercialization

The Purdue Innovates Office of Technology Commercialization operates one of the most comprehensive technology transfer programs among leading research universities in the U.S. Services provided by this office support the economic development initiatives of Purdue University and benefit the university’s academic activities through commercializing, licensing and protecting Purdue intellectual property. In fiscal year 2024, the office reported 145 deals finalized with 224 technologies signed, 466 invention disclosures received and 290 U.S. and international patents received. The office is managed by the Purdue Research Foundation, which received the 2019 Innovation and Economic Prosperity Universities Award for Place from the Association of Public and Land-grant Universities. In 2020, IPWatchdog Institute ranked Purdue third nationally in startup creation and in the top 20 for patents. The Purdue Research Foundation is a private, nonprofit foundation created to advance the mission of Purdue University. Contact otcip@prf.org for more information.

Sources: Nature Communications 

Krishna Jayant, kjayant@purdue.edu