Parkinson’s disease (PD) is one of the highly prevalent neurodegenerative diseases which lack a specific diagnosis for the clinical evaluation of disease progression as well as its treatment. A novel research study revealed that detection of αSyn aggregates circulating in the cerebrospinal fluid (CSF) may provide an opportunity for a sensitive and specific biochemical diagnosis of PD.
Parkinson’s disease (PD) is one of the degenerative disorders caused by aggregation and deposition of α-synuclein (αSyn) in the brain and leads to abnormalities in the motor activities and gait pattern. Usually, α-synuclein follows a seeding-nucleation mechanism that depends on the slow formation of seeding-competent oligomers followed by the exponential growth of the polymers to form long fibrils that misfold and accumulate in the damaged cells. Therefore, detection of soluble misfolded αSyn oligomers in biological fluids would represent a good strategy for biochemical diagnosis of PD. In spite of identifying biochemical markers for PD, there is an absence of an accepted and validated surrogate biomarker. Therefore, efforts have been made for the availability of a sensitive, specific, and noninvasive biochemical marker for the diagnosis and monitoring of disease progression as well as early identification of neurodegenerative diseases. In this direction, Soto and his team have provided a novel procedure for specific detection of αSyn aggregates in biological fluids of PD and other synuclein aggregation disorders. The findings of the seeding-nucleation process for detecting the misfolded oligomers of αSyn were published in JAMA Neurology, 2016.
Over the past, seeding protein misfolding cyclic amplification (PMCA) has been extensively used for understanding biology, mechanisms and ultrasensitive detection of prions (infectious protein particles) in biological fluids. In the present study, researchers have adapted PMCA for the highly sensitive detection of αSyn aggregates (αSyn-PMCA) in cerebrospinal fluid (CSF) samples of those affected by PD and those of individuals with other neurologic diseases from 2013 to 2015. The study subjects obtained from Japan and Germany constituted CSF samples of patients suffering from PD (n=76) and controls affected by other neurologic disorders (n = 65), neurodegenerative diseases (n = 18), and Alzheimer disease (n = 14). The αSyn-PMCA assays revealed the kinetics of αSyn aggregation which was correlated with disease severity. Interestingly, evaluation of synthetic αSyn aggregates showed that αSyn-PMCA enabled the detection of αSyn oligomers at low levels (0.1 pg/mL), indicating that the αSyn-PMCA signal was directly proportional to the amount of αSyn oligomers added to the reaction. In addition, the blinded study of CSF samples correctly identified PD patients with an overall 88.5% sensitivity and 96.9% specificity from other neurological diseases. Also, the findings of the Japanese and German cohort revealed αSyn-PMCA results were correlated with the severity of the clinical symptoms of PD.
Therefore, a biochemical diagnostic procedure is a useful tool in monitoring the progression of the disease, providing targets for novel treatments and their potential mechanism of action. In summary, PMCA is a platform technology which is employed to detect the presence of misfolded aggregates of proteins circulating in the biological fluids of those with neurodegenerative diseases. In addition to the pathological confirmation of PD, the PMCA method’s ability to differentiate PD αSyn from other synucleinopathies, and optimization of blood-based αSyn-PMCA, would further optimize the clinical evaluation of PD. Therefore, prion proteins combined with PMCA, Aβ-PMCA, and αSyn-PMCA along with tau and TDP-43 aggregates would be a probable complete panel of tests for screening and diagnosing neurodegenerative diseases as well as development of patient-specific therapeutic interventions.
Written By: Manche Santoshi, PhD