Recently, in a study published in Nature, researchers from the University of Pennsylvania have found that the main features of different Parkinson‘s-related brain disorders may be intracellular misfolded proteins; the authors found that the pathological form of α-synuclein is the culprit in the induction of many diseases.

 

Dr. Chao Peng said that the influence of cell types on different α-synuclein variants may be able to solve the most important mystery in the study of neurodegenerative diseases. Now Researchers have not described the association between cell types and multiple disease proteins in multiple neurodegenerative brain diseases, but their only hope so far is that a protein associated with multiple system atrophy (MSA) may be expected to help develop novel therapies for neurodegenerative diseases.

 

 

The researchers said that α-synuclein is present in patients with Parkinson’s disease with or without dementia, dementia with Lewy bodies (LBs), and about 50% of Alzheimer’s patients. MSA is a very rare neurodegenerative disease that has a wide range of effects on the patient’s brain and body. However, α-synuclein does not act in the same way. It mainly accumulates outside the nucleus of oligodendrocytes to form glial cytoplasmic contents (GCIs). Oligodendrocytes are a kind of important brain structural cells, which are important for the production of myelin.

 

The researchers found that pathological α-synuclein is not identical in shape and biological characteristics in LBs and GCIs, and that α-synuclein in GCIs can form a very compact structure, and in animal models the potential for spreading and diffusing α-synuclein aggregation can be increased by a factor of 1000, which may be consistent with highly invasive MSA. Researcher Dr. Virginia M.-Y. Lee pointed out that, years ago, we discovered that α-synuclein fibrils can play a “seed” role in inducing α-synuclein aggregation to form mass-like structures. Fibers can be absorbed by healthy neurons, forming Lewy bodies and dystrophic neurites, thereby damaging the function of neurons and leading to neuronal cell death.

 

When human brain-derived α-synuclein is induced to accumulate in cell cultures and mouse models, pathological α-synuclein in LBs and GCIs may not have a preference for certain types of cells when starting pathological performances; the researchers then wondered why pathological α-synuclein in Parkinson’s disease and multiple atrophy showed different potentials, properties, and distributions in neurons and glial cells.

 

In addition, the researchers also found that oligodendrocytes (not neuronal cells) may have the ability to transform misfolded α-synuclein into cytoplasmic proteins, this, however, may explain the distribution of two different proteins in the same cell type. On the other hand, cytoplasmic α-synuclein can maintain its active spreading function when transmitted between neurons, therefore, the investigators concluded that misfolded α-synuclein “seeds” and cell types may determine the form of α-synuclein.

 

Next, the researchers hope to understand the molecular mechanism of the emergence of different types of α-synuclein. Specific molecules that are responsible for the formation of high-potential cytoplasmic α-synuclein in oligodendrocytes may serve as a novel drug target for the treatment of MSA, and this may also help explain why therapies to treat other synucleionpathies may not be effective for MSA patients.

 

 

Reference

Chao Peng, Ronald J. Gathagan, Dustin J. Covell, et al. Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature (2018) doi:10.1038/s41586-018-0104-4