Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

Abstract

Clathrin mediated endocytosis (CME) is the best characterized mechanism governing cellular membrane-and protein trafficking. In this hypothesis review, we integrate recent evidence implicating CME and related cellular trafficking mechanisms in the pathophysiology of psychotic disorders such as schizophrenia and bipolar disorder. The evidence includes proteomic and genomic findings implicating proteins and genes of the CME interactome. Additionally, several important candidate genes for schizophrenia, such as dysbindin, are involved in processes closely linked to CME and membrane trafficking. We discuss that key aspects of psychosis neuropathology such as synaptic dysfunction, white matter changes, and aberrant neurodevelopment are all influenced by CME, and that other cellular trafficking mechanisms previously linked to psychoses interact with CME in important ways. Furthermore, many antipsychotic drugs have been shown to affect clathrin-interacting proteins. We propose that the targeted pharmacological manipulation of CME may offer fruitful opportunities for novel treatments of schizophrenia.

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

“…According to Schubert el al. [38], clathrin influences processes such as synaptic dysfunction, white matter changes, and aberrant neurodevelopment and consequently may be related to schizophrenia pathology. We found differential expression of the light and medium neurofilaments (NEFL and NEFM), as did Sivagnanasundaram et al [25].…”

Maternal Immune Activation Induces Changes in Myelin and Metabolic Proteins, Some of Which Can Be Prevented with Risperidone in Adolescence

“…We also specifically tested differentially proteins implicated in recent proteomic reviews of schizophrenia studies [6,51,67] ( table 3 ). Of the 28 candidate proteins identified in these reviews, over 55% (15 individual proteins) were found to be differentially expressed by prenatal poly(I:C).…”

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

“…Therefore, the careful integration of information derived from pathway analysis into known clinical, epidemiological, pathological and pathophysiological correlates of disorders is paramount if meaningful novel hypotheses are to be derived from -omics technologies. We have taken this approach previously discussing the role of clathrinmediated endocytosis in psychotic disorders (Schubert et al, 2012), and the present study, focusing on hippocampal GABAergic interneuron pathology, has followed the same principles.…”