Alpha-synuclein (aSyn), a protein linked to Parkinson’s disease and dementia with Lewy bodies (DLB), exerts its harmful effects by disrupting the normal function of protein production, a study has found.
This sheds light on the involvement of the aSyn protein in Parkinson’s disease, confirming its potential as a therapeutic target.
The study, “Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function,” was published in the journal Neurobiology of Disease.
Alpha-synuclein plays a key role in both Parkinson’s disease and DLB. This protein is the major component of Lewy bodies — protein clumps that develop inside nerve cells and contribute to neurodegeneration.
Mutations in the gene that provides instructions for making aSyn protein, the SNCA gene, are linked to familial forms of Parkinson’s disease. This is especially true for a mutation known as A30P.
These cellular structures work together and function as the body’s “postal service” by targeting and “packaging” newly produced proteins. They make sure these are delivered to their proper destination.
To understand the impact of the A30P mutation on aSyn production and on other cell functions and structures, including the endoplasmic reticulum and Golgi complex, an international team of researchers used a mouse that harbored the A30P mutation in the SNCA gene.
This allowed researchers to compare the expression of several genes in this mouse with another one that produced the healthy version of the aSyn protein. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.
Researchers found that the transcription — the first step in protein production (DNA to RNA) — of several genes was deregulated in the mouse that had the A30P mutation.
In particular, the COL4A2 gene, which codes for collagen — a protein that gives form to some tissues, including the skin — was highly expressed in the A30P mouse model.
This trend was confirmed in human nerve cells that also carried the A30P mutation. Collagen is present in several membranes within the body, including the blood brain barrier, a semipermeable membrane that protects the brain from outside factors.
This overexpression was associated with lower levels of a particular molecule, called a micro-RNA, that specifically regulates and controls levels of the COL4A2 gene. These results suggest a crucial role for collagen-related genes and dysfunction in basement membranes such as the blood brain barrier in aSyn toxicity.
In human nerve cells, mutated aSyn also altered the structure of the Golgi complex and made the endoplasmic reticulum more vulnerable to stress conditions. Several studies have implicated endoplasmic reticulum stress in the development of neurodegenerative diseases.
The researchers said that he findings provide new insights “into the putative role of aSyn on transcriptional deregulation, thereby uncovering novel targets for therapeutic intervention in [Parkinson’s] and other synucleinopathies.”