Cerebrospinal fluid proteomics implicates the granin family in Parkinson’s disease

Abstract

Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Better understanding of the underlying disease mechanism(s) is an urgent need for the development of disease-modifying therapeutics. Limited studies have been performed in large patient cohorts to identify protein alterations in cerebrospinal fluid (CSF), a proximal site to pathology. We set out to identify disease-relevant protein changes in CSF to gain insights into the etiology of Parkinson's disease and potentially assist in disease biomarker identification. In this study, we used liquid chromatography-tandem mass spectrometry in dataindependent acquisition (DIA) mode to identify Parkinson's-relevant biomarkers in cerebrospinal fluid. We quantified 341 protein groups in two independent cohorts (n = 196) and a longitudinal cohort (n = 105 samples, representing 40 patients) consisting of Parkinson's disease and healthy control samples from three different sources. A first cohort of 53 Parkinson's disease and 72 control samples was analyzed, identifying 53 proteins with significant changes (p < 0.05) in Parkinson's disease relative to healthy control. We established a biomarker signature and multiple protein ratios that differentiate Parkinson's disease from healthy controls and validated these results in an independent cohort. The second cohort included 28 Parkinson's disease and 43 control samples. Independent analysis of these samples identified 41 proteins with significant changes. Evaluation of the overlapping changes between the two cohorts identified 13 proteins with consistent and significant changes (p < 0.05). Importantly, we found the extended granin family proteins as reduced in disease, suggesting a potential common mechanism for the biological reduction in monoamine neurotransmission in Parkinson's patients. Our study identifies several novel protein changes in Parkinson's disease cerebrospinal fluid that may be exploited for understanding etiology of disease and for biomarker development.

Fibrinogen and Complement Factor H are promising CSF protein biomarker(s) for Parkinson’s disease with cognitive impairment- A Proteomics and ELISA based study

“…NPTXR, [50] a transmembrane synaptic protein, is decreased in CSF of AD patients with severe cognitive impairment [51], hence the higher levels in our samples confirm normal cognition in PD. The significant down-regulation in SCG3 in PDCI contrasted by an increase in SCG2 in PD supports the hypothesis of catecholaminergic deficit in the later stages of PD [52,53]; which is often riddled with cognitive impairment. CHI3-L1 being associated with neuroinflammation [54] and faster cognitive decline, its increase in PD-CSF hints at the likely progress into cognitive impairment.…”

Can we put Humpty Dumpty back together again? What does protein quantification mean in bottom-up proteomics?

“…Along these same lines, a study of cerebrospinal fluid in Parkinson's disease found that quantification of specific tryptic peptides was differential in affected individuals compared to healthy, age-matched controls. Specifically, peptides in the C-terminal or N-terminal regions of granin family proteins were found to be decreased in Parkinson's (21). Importantly, the granin family of proteins is known to play a role in regulating secretion and delivery of peptides and neurotransmitters and are known to be processed into a number of derived bioactive peptides (Figure 5).…”

Cerebrospinal Fluid Levels of Chromogranin A in Parkinson’s Disease and Multiple System Atrophy

“…In the patients with early and advanced PD lower levels of CSF CgA have been found [ 7 , 8 , 10 ]. Rotunno et al measured various proteins from the granin family in the CSF of PD patients as potential biomarkers; CgA was found to be decreased [ 11 ]. Studies concerning serum CgA in PD produced contradictory results.…”