Abnormal Transcytosis Mechanisms in the Pathogenesis of Hydrocephalus: A Review

Abstract

Hydrocephalus is a chronic neurological condition caused by abnormal cerebrospinal fluid (CSF) accumulation, significantly impacting patients' quality of life. Its causes remain poorly understood, making neurosurgery the primary treatment. Research suggests that hydrocephalus may result from impaired macromolecular clearance, leading to increased osmotic load in the ventricles. Macromolecules are cleared via processes such as transcytosis, involving caveolae- and clathrin-dependent pathways, soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins, and vesicular trafficking. Abnormalities in transcytosis components, such as mutations in alpha-SNAP (α-soluble NSF attachment protein) and SNARE complexes, disrupt membrane organization and vesicle fusion, potentially contributing to hydrocephalus. Other factors, including alpha-synuclein and Rab proteins, may also play roles in vesicle dynamics. Insights from animal models, such as hyh (hydrocephalus with hop gait) mice, highlight the pathological consequences of these disruptions. Understanding transcytosis abnormalities in hydrocephalus could lead to novel therapeutic strategies aimed at enhancing macromolecular clearance, reducing ventricular fluid buildup, and improving patient outcomes.

Keywords: SNARE proteins; efflux transporters; hydrocephalus; hyh mice; macromolecular transport; membrane fusion; osmolarity gradients; pathogenesis of hydrocephalus; transcytosis; vesicle trafficking.

Figure 1

Simplified Diagram of Transcytosis [1,13].

Figure 2

Different mediating factors of each step in transcytosis [13,14].

Figure 3

The SNARE Hypothesis [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28].

Figure 4

The Structure of Alpha-Synuclein [21,42,44].

Figure 5

Types of Liposomes [21].

Figure 6

Membrane-Bound Alpha-Synuclein [21,44].

Figure 7

Different types of SNAREs [23].

Figure 8

Vesicle Fusion mediated by SNAREs [24,25].

Figure 9

Role of Munc Proteins in Exocytosis [27].

Figure 10

Generalised Structure of Rab Proteins [28,52]. From [52], reprinted with permission from AAAS.

Figure 11

Cycling of Rab Proteins and Functions of Rab Proteins—Molecular Switch; Cargo Selection and Vesicle Formation; Vesicle Movement; Vesicle Uncoating; Vesicle Tethering; and Membrane Fusion [17,28,54,55,56,57,58].