Proteome Profiling of the Dura Mater in Patients with Moyamoya Angiopathy

Abstract

Moyamoya angiopathy (MMA) is an uncommon cerebrovascular disease characterized by a progressive steno-occlusive lesion of the internal carotid artery and the compensatory development of an unstable network of collateral vessels. These vascular hallmarks are responsible for recurrent ischemic/hemorrhagic strokes. Surgical treatment represents the preferred procedure for MMA patients, and indirect revascularization may induce a spontaneous angiogenesis between the brain surface and dura mater (DM), whose function remains rather unknown. A better understanding of MMA pathogenesis is expected from the molecular characterization of DM. We performed a comprehensive, label-free, quantitative mass spectrometry-based proteomic characterization of DM. The 30 most abundant identified proteins were located in the extracellular region or exosomes and were involved in extracellular matrix organization. Gene ontology analysis revealed that most proteins were involved in binding functions and hydrolase activity. Among the 30 most abundant proteins, Filamin A is particularly relevant because considering its well-known biochemical functions and molecular features, it could be a possible second hit gene with a potential role in MMA pathogenesis. The current explorative study could pave the way for further analyses aimed at better understanding such uncommon and disabling intracranial vasculopathy.

Multi‐omic approaches for biomarker discovery in Moyamoya disease

“…In this regard, multi‐omic approaches may turn out to be crucial in patients’ risk stratification and precision medicine, allowing for the selection and customization of medical treatment based on individual signatures. In addition, combining multiple omics strategies may also shed light on potential novel targets for MMD therapeutic intervention, as shown above for FLNA and LPC 6,7,10 …”

“…Interestingly, the quantitative analysis revealed that Filamin A (FLNA) was significantly up‐regulated in all MMD subgroups when compared to control subjects. Such evidence is particularly relevant if considering the results obtained through a comprehensive, label‐free, quantitative MS‐based proteomic characterization of dura mater samples from MMD patients 7 . Indeed, exactly FLNA emerged among the most abundant detected proteins and was indicated as a second hit gene in MMD pathogenesis, by promoting MMD‐like vascular formation.…”

“…Such evidence is particularly relevant if considering the results obtained through a comprehensive, label-free, quantitative MS-based proteomic characterization of dura mater samples from MMD patients. 7 Indeed, exactly FLNA emerged among the most abundant detected proteins and was indicated as a second hit gene in MMD pathogenesis, by promoting MMD-like vascular formation. It is a large actin-binding protein, important for cell motility due to providing scaffolds for multiple cytoskeletal proteins.…”

“…In addition, combining multiple omics strategies may also shed light on potential novel targets for MMD therapeutic intervention, as shown above for FLNA and LPC. 6,7,10…”

Multiomics and blood-based biomarkers of moyamoya disease: protocol of Moyamoya Omics Atlas (MOYAOMICS)

“…The upregulation of haptoglobin and A1BG in MMD patients' cerebrospinal fluid suggests potential roles in inflammation and angiogenesis, making them promising novel biomarkers for further investigation [ 21 ]. Moreover, serum proteomics has revealed dysregulated lipid metabolism in both ischemic and hemorrhagic MMD patients, emphasizing its significance in vascular changes [ 22 ].In addition, the characterization of proteins in Moyamoya angiopathy (MMA) between the brain surface and dura mater has identified Filamin A as a potential key player, offering initial insights into MMA’s unique intracranial vasculopathy [ 23 ]. Investigation into RNF213’s role in MMD and antimicrobial activity has highlighted changes in proteins like MVP, CYR61, and DDAH1 upon RNF213 knockdown, suggesting potential connections between RNF213, immune responses, and MMD development, possibly involving nitric oxide production in combating Listeria infection [ 24 ].…”