by Anushri Bhattacharya
Parkinson’s Disease (PD), which is the second most widely prevalent progressive neurodegenerative disorder after Alzheimer’s, affects around 10 million people worldwide. In Parkinson’s disease, lesions to the neurons in the central nervous system weaken their ability to produce dopamine which affects the proper functioning of the brain and thus, affects the movement in patients, and often cause tremors, stiffness, loss of balance along with loss of their sense of smell and taste which are usually the early symptoms of PD. This has in fact led to a recent study topic: “SARS-CoV-2 proteins- possible link to a protein related to Parkinson’s Disease?”. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as we all know has led to a pandemic in the world today that is- it causes an infectious and easily communicable, respiratory disease called coronavirus disease 19 (COVID-19) which includes common symptoms such as fever, tiredness, headaches, cough, loss of taste or smell and sometimes ‘brain fog’ in severe cases. Now, how exactly is it that PD and SARS-CoV-2 may be linked together?
Several studies have reported that usually older patients, who were affected with SARS-CoV-2 virus have displayed neurological events apart from respiratory complications. For instance, acute cerebrovascular disease (CVD) following COVID-19, was found common (around 38%) in elderlies as they had developed a stroke in lobar locations of the brain; moreover, impaired consciousness and typical motor and non-motor symptoms related to PD have also been demonstrated in some COVID-19 patients. Additionally, some reports have stated wherein relatively young COVID-19 patients have demonstrated symptoms of Parkinson’s disease within 2-5 weeks of being infected with the SARS-Cov-2 virus. Moreover, fascinatingly, the symptom of losing the sense of smell in COVID-19 is also seen in PD, as it is a common premotor symptom in Parkinson’s disease. These facts have paved a way for the researchers of ACS Chemical Neuroscience to carry out test-tube experiments to find out whether the 2 diseases could be after all relatable or not. The main aim of these experiments was to answer the controversial question: “Whether the severe symptoms of the COVID-19 affecting the brain is caused directly by the virus or by the chemical signals which are released by the immune system while fighting the virus ?”
To answer the above question, we’ll have to know some background information about complex proteins related to PD and SARS-CoV-2. Firstly, most synucleinopathies or brain disorders characterised by the formation of inclusions in cell bodies or axons caused due to the accumulation of a protein called alpha-synuclein (aS), are diagnosed by the aggregate aS deposition. Thus, a-synuclein which is a soluble neuronal protein is a major component of all synucleinopathies including Parkinson’s disease. In PD, aggregation, accumulation, and misfolding of this neuronal protein (aS), caused due to various genetic and neuropathological factors, leads to the formation of abnormal amyloid fibrils which are insoluble protein structures that are resistant to degradation hence are harmful. The formation of amyloid fibrils due to the aggregate of a-synuclein makes PD a type of amydiosis. The formation of the amyloid fibrils leads to the degeneration of dopaminergic neurons in the midbrain which in turn leads to depletion of dopamine levels, thereby negatively affecting the brain's ability to function, hence progressing parkinsonism. Now speaking of SARS-CoV-2, there are 2 major proteins related to the virus- firstly, the spike (S-) protein that aids the virus in initiating the infection by penetrating the host cell; and secondly, the nucleocapsid (N-) protein that packages the RNA-genome to form ribonucleoprotein structures which are vital for the survival of the virus.
In the test-tube experiment conducted by the researchers, the most abundant proteins of the SARS-CoV-2 (S-protein and N-protein(90%)) were chosen to interact with the a-synuclein protein of PD. To draw conclusions, 2 conditions were created- the rate of aggregation of a-synuclein in the absence & presence of coronavirus proteins. A fluorescent probe that binds with the amyloid fibrils was used to determine the time taken for the a-synuclein to aggregate into fibrils in each case. The results showed that in the absence of SARS-CoV-2 proteins, the aS took >240 hours to aggregate into fibrils, however in the presence of the S-protein no change was observed, but adding the N-protein showed a significant increase in the rate as it took <24 hours for the a-synuclein to aggregate into fibrils. Thus, we can say that the presence of the N-protein of SARS-Cov-2 acted as a catalyst in the aggregation of a-synuclein to form amyloid fibrils. Moreover, in a parallel experiment, it was observed that there was direct interaction between the N-protein and a-synuclein due to their opposite electrostatic charges. Additionally, in another experiment, a cell model of Parkinson’s disease was used in 2 conditions :
1) The cell model of PD was injected with concentrations of N-protein as expected in coronavirus infected cells along with a-synuclein which were fluorescently labelled.
2) The cell model of PD was injected with only a-synuclein as it was the control group
Results showed that in condition (1) with both proteins, double the amount of cells died in contrast to condition (2) which was injected with only PD protein-aS. It was also observed that in the treatment condition (1), the normal distribution of a-synuclein in the cell was disrupted and the formation of elongated structures took place, however, the researchers couldn't confirm whether these structures were amyloid fibrils.
In conclusion, although these experiments are test-tube based, they show some significant results which can be possibly used in the future to establish a relation between SARS-CoV-2 and Parkinson’s disease, that is whether SARS-CoV-2 protein (N-protein) triggers the formation of amyloid fibrils due to aggregation of a-synuclein neuronal protein as in Parkinson’s disease and whether these interactions take place within the neurons of our brain as well!
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