CLIC1 Protein Accumulates in Circulating Monocyte Membrane during Neurodegeneration

Abstract

Pathologies that lead to neurodegeneration in the central nervous system (CNS) represent a major contemporary medical challenge. Neurodegenerative processes, like those that occur in Alzheimer’s disease (AD) are progressive, and at the moment, they are unstoppable. Not only is an adequate therapy missing but diagnosis is also extremely complicated. The most reliable method is the measurement of beta amyloid and tau peptides concentration in the cerebrospinal fluid (CSF). However, collecting liquid samples from the CNS is an invasive procedure, thus it is not suitable for a large-scale prevention program. Ideally, blood testing is the most manageable and appropriate diagnostic procedure for a massive population screening. Recently, a few candidates, including proteins or microRNAs present in plasma/serum have been identified. The aim of the present work is to propose the chloride intracellular channel 1 (CLIC1) protein as a potential marker of neurodegenerative processes. CLIC1 protein accumulates in peripheral blood mononuclear cells (PBMCs), and increases drastically when the CNS is in a chronic inflammatory state. In AD patients, both immunolocalization and mRNA quantification are able to show the behavior of CLIC1 during a persistent inflammatory state of the CNS. In particular, confocal microscopy analysis and electrophysiological measurements highlight the significant presence of transmembrane CLIC1 (tmCLIC1) in PBMCs from AD patients. Recent investigations suggest that tmCLIC1 has a very specific role. This provides an opportunity to use blood tests and conventional technologies to discriminate between healthy individuals and patients with ongoing neurodegenerative processes.

Transmembrane Chloride Intracellular Channel 1 (tmCLIC1) as a Potential Biomarker for Personalized Medicine

“…Since soluble and fibrillar Aβ are both able to induce ROS production in microglia it is reasonable to think that this is the cellular subtype where tmCLIC1 inserts forming a functional channel. In a recent study it was shown that peripheral blood mononuclear cells (PBMC) and, in particular, monocytes, isolated from Alzheimer’s Disease patients show an overexpression of CLIC1 mRNA that is accompanied by a significative increase in transmembrane protein [ 50 ]. The authors concluded that the study could pave the way for future developing strategies aimed at discriminating between healthy and patients with ongoing neurodegenerative processes.…”

The Phenome-wide Consequences of Anorexia Nervosa Genes

“…CLIC1 (Chloride Intracellular 1) encodes a chloride ion channel protein involved in many necessary cellular functions including the regulation of cell membrane potential, and the proliferation and differentiation of cells(57), including a role in axonal outgrowth of neurons 51 . In addition to neurons, CLIC1 has been found to be expressed in many different tissue types(59), and in particular, CLIC1 protein has been found to accumulate in peripheral blood mononuclear cells (PBMCs) when the central nervous system is in a state of chronic inflammation(58), and increased CLIC1 expression has been shown to occur in microglia stimulated by the presence of β-amyloid in vitro (60,61). Therefore, CLIC1 may potentially act as a biomarker for neurodegenerative disorders such as Alzheimer’s disease, and downregulation of CLIC1 has been shown to have a neuroprotective effect in the presence of β-amyloid proteins(58,60–62).…”

“…In addition to neurons, CLIC1 has been found to be expressed in many different tissue types(59), and in particular, CLIC1 protein has been found to accumulate in peripheral blood mononuclear cells (PBMCs) when the central nervous system is in a state of chronic inflammation(58), and increased CLIC1 expression has been shown to occur in microglia stimulated by the presence of β-amyloid in vitro (60,61). Therefore, CLIC1 may potentially act as a biomarker for neurodegenerative disorders such as Alzheimer’s disease, and downregulation of CLIC1 has been shown to have a neuroprotective effect in the presence of β-amyloid proteins(58,60–62). Variants in CLIC1 may contribute to risk of multiple psychiatric disorders and behaviors, such as schizophrenia, MDD and PTSD, as well as many autoimmune and immune-related phenotypes such as asthma and systemic lupus erythematosus(50–53),(63) ( Table S5 ).…”

Altered gene expression and PTSD symptom dimensions in World Trade Center responders

“…Studies have suggested it might play a role in DNA damage repair and nucleocytoplasmic RNA transport. CLIC1 has been implicated in other psychiatric disorders, but its primary function is inflammasome regulation 69–71 . In addition, 6/10 genes had highly consistent directions of effect.…”