Dr. Shu ChenShu Chen, Ph.D., Ona Faye-Petersen Endowed Professor in the Division of Neuropathology, and Anupam Raina, Ph.D., a postdoctoral fellow in the Chen lab, co-authored a manuscript that was recently selected as an “Editors’ Pick” by the Journal of Biological Chemistry. The paper, titled, “Skin-derived α-synuclein strains from PD, DLB, and MSA induce distinct intracellular pathology and neurodegeneration,” was selected by the editors for its exceptional contribution to the field.

The study focuses on α-synuclein, a protein known to form harmful clumps in the brain. When α-synuclein misfolds into different shapes, also known as strains, it can cause neurodegenerative diseases such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. While misfolded α-synuclein is commonly found in the brains of affected patients, researchers have detected it in their skin samples, creating new opportunities for studying these diseases outside of the nervous system.Dr. Anupam Raina

Using a test called the real-time-quaking-induced conversion (RT‑QuIC) assay, scientists revealed that α-synuclein strains from patient skin samples are highly active and capable of starting clump formation. This process, known as seeding, occurs when misfolded protein strains enter cells and act as a template, causing normal form of α-synuclein protein to misfold as well. Over time, as this process spreads and multiplies, it results in harmful clumps forming throughout the cell.

To test whether the patient skin-derived strains could cause pathological changes, Chen and Raina, together with their collaborators used a human cell line known as U251. Their experiments found that α-synuclein strains formed insoluble and toxic protein inclusions inside cells.

“To our knowledge, this is the first study showing that patient skin-derived α-synuclein strains are pathological like the brain-derived strains,” Raina said.

The team engineered a Förster resonance energy transfer (FRET)-based α-synuclein biosensor in U251 cells to track and identify how these clumps formed. Results showed that strains from Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy patients triggered intracellular clumping with distinct differences. All three types of skin-derived strains were found to be bioactive and trigger the degeneration of neurons, the cell type that are damaged in the diseased brains.

“Our study provides a cell-based platform to better characterize α-synuclein strains from patient skin,” Chen said. “This platform could also potentially be used to screen drugs for treating patients affected by these neurodegenerative diseases.”