Alpha-synuclein (α-Syn) is a cellular protein with several functions and scientists know form som time now that it is partially responsible for the cellular degeneration seen in certain brains area hit by the disease. The protein α-Syn is predominantly expressed in neurons than astrocytes and other neural cells, and is associated with neurodegenerative diseases like Parkinson’s disease (PAD) itself and dementia with Lewy bodies (LBD). Studies have reported the role of α-Syn in dendritic outgrowth, branching and spine density and maturation specifically for hippocampal neurons. There is indeed a line of thought that deem PAD being an unbalanced turnover between a dying substantia nigra and an hippocampus unable to renew the neuronal loss with its migratory neurogenesis. Indeed, in the past decade, PD research has successfully demonstrated that early-stage neuronal loss originates in the hippocampus and olfactory bulb, rendering neurogenesis research in these brain regions particularly interesting.
Like in Alzheimer, the neuronal death involved in PAD begins with axonal degradation. Many of the debilitating motor symptoms associated with PD stem from the degeneration of nigrostriatal DA neurons, whose axons bridge the substantia nigra pars compacta and caudate putamen regions of the brain, PAD pathogenesis is driven by the aggregation of α-syn into Lewy bodies (misfolded protein tangles) and neurites and the eventual loss of dopaminergi neurons. As a result, much of the research related to achieving neuroprotection in PAD has focused on preventing neuronal death, rather than reversing axonal degeneration. The importance of axonal degradation over programmed cell death in early PAD pathology, may explain the failure of anti-apoptotic kinase inhibitors to prevent disease progression, as these neuroprotective agents do not confer any sort of axonal protection or regenerative influence. Indeed, currently, there are no actual disease modifying therapies for Parkinson’s disease that can change the progression of the disease.
An international team of scientists led by professo David Beckham, MD, at the University of Colorado Anschutz Medical Campus is hoping to change that. Today, they published new research in the journal Brain, that takes scientists one step closer to understanding a key protein α-synuclein that they found links inflammation and Parkinson’s disease.This new study identifies the novel mechanism that links interferon activation and α-Syn function in neurons as a potential trigger for developing Parkinson’s disease. To investigate the mechanism of immune responses to viral infections in the brain induced by α-Syn, the researchers challenged αSyn knock-out (KO) mice and human αSyn KO dopaminergic neurons with RNA viruses. They discovered that αSyn is required for neuronal expression of interferon-stimulated genes (ISGs). They then found that following any stimulus that triggers interferon signals, a type of immune response, α-Syn interacts with signaling proteins in neurons to trigger expression of ISGs. The authors mention that this data confirms that α-Syn responds to infection and inflammatory pathways.
The next important step is to determine if the interactions between interferon and α-Syn trigger the formation of the toxic forms of misfolded α-Syn, called fibrils, that have been found in Parkinson’s disease. This work provides the first clear mechanism that links inflammation and a-Syn, There are also parallel studies that indicate how α-Syn may travel from damaged neurons and spread among the brain matter theough exosomes, cellular vescicles enriched in proteins, nucleic acids and other bioactive molecules. The aggregated proteins (fibrils/tangles) would use exosomes as Tojan horses, corroborating the original theory stating that PAD would “travel” far way from the original spring, by diffusing a pathological form of α-Syn. Siding this theory there are proofs accumulated in the last 5 years mounting evidence of how α-Syn would use retrograde axonal transport through the vagus nerve, to put in communication the gut with the central nervous system.
The fact that this latest research also discovered how α-Syn might enhance the synthesis of immune-regulated genes, strenghtens the latest hypothesis put in the field, i.e. that PAD has an immunological component. However, if immune dysregulation is the trigger or a consequence is still unknown. The researchers suggest future studies are needed to look into the interactions between type 1 interferon signals in neurons and misfolded α-Syn. The goal is to determine if drugs that inhibit these interactions can prevent the formation of misfolded α-Syn. This would result in a revolutionary disease-modifying therapeutic approach for the patients.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Advised in this website
Monogue B et al., Beckham JD. Brain. 2022 Jul 21:awac192.
Wakhloo D et al. Neural Regen Res 2022; 17(12):2606-2614.
Li KL et al. Neural Regen Res. 2022; 17(9):1898-1906.
J Neurol. 2022 Jul 13:1-25.
Dott. Gianfrancesco Cormaci
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