The clusterin protein, also known as apolipoprotein J (ApoJ), is a widely distributed glycoprotein found throughout the human body. First identified in 1983 in ram rete testis fluid, it was named for its ability to cause cell “clustering.” Clusterin is present in various tissues and bodily fluids, including blood, cerebrospinal fluid, and numerous organs.
Understanding Clusterin’s Functions
Clusterin acts as a molecular chaperone, maintaining the proper shape of other proteins and preventing them from clumping together. Unlike many chaperones that work inside cells, clusterin is primarily secreted and functions in the extracellular environment, neutralizing the toxicity of misfolded proteins. It binds to misfolded proteins and facilitates their uptake by cells for degradation in lysosomes.
The protein also participates in programmed cell death, or apoptosis, exhibiting a dual role, promoting or inhibiting this process depending on cellular conditions. For example, a secreted form of clusterin may protect cells from stress-induced apoptosis by interacting with specific pathways. Conversely, an intracellular form localized to the nucleus has been observed to trigger apoptosis.
Clusterin is involved in lipid transport, particularly in the brain where it serves as a key cholesterol transport lipoprotein. It shares characteristics with apolipoprotein E (APOE) in its involvement in lipid transport. Clusterin also contributes to immune regulation and cell adhesion, binding to bacteria and facilitating the clearance of late apoptotic cells by macrophages, which helps maintain immune tolerance.
Clusterin’s Involvement in Disease
Dysregulation or altered levels of clusterin are linked to various human diseases, including neurodegenerative conditions. In Alzheimer’s disease (AD), clusterin binds to amyloid-beta (Aβ) peptides and can influence plaque formation and clearance. While some studies suggest clusterin helps clear Aβ across the blood-brain barrier, other research indicates it might also contribute to Aβ neurotoxicity and AD progression.
Clusterin’s involvement extends to Parkinson’s disease (PD), a neurodegenerative disorder characterized by the aggregation of alpha-synuclein (α-Syn). Clusterin can inhibit the aggregation of various proteins, including α-Synuclein. Its expression is often upregulated in the plasma and cerebrospinal fluid of PD patients, suggesting clusterin may play a role in the cell’s response to α-Synuclein burden.
In cancer, clusterin exhibits a complex and sometimes contradictory role, acting as both a promoter of tumor growth and metastasis, and at other times, as a tumor suppressor. Its overexpression in various cancers is associated with promoting tumor cell survival, resistance to therapies, and processes like epithelial-mesenchymal transition (EMT) that facilitate metastasis. However, a cytoplasmic form of clusterin has been shown to suppress lung cancer metastasis, indicating its varied functions based on cellular location.
Beyond neurodegenerative diseases and cancer, clusterin is also connected to kidney diseases, cardiovascular conditions, and chronic inflammatory disorders. In acute kidney injury, clusterin can suppress macrophage infiltration and inflammation during recovery, and enhance phagocytic activity, which may contribute to tissue repair. Increased clusterin levels have been observed in plasma and the left ventricle after myocardial infarction, suggesting a protective effect by reducing apoptosis in cardiac cells. Clusterin is also associated with systemic and synovial inflammation in conditions like knee osteoarthritis.
Clusterin as a Biomarker and Therapeutic Target
Clusterin’s potential in medical diagnostics is being investigated as a biomarker for disease progression or severity. Clusterin levels in cerebrospinal fluid (CSF) and blood plasma are being explored for their association with neurodegenerative diseases like Alzheimer’s and Parkinson’s. For instance, higher baseline clusterin levels in CSF have been linked to a higher rate of Aβ accumulation in individuals with mild cognitive impairment.
In cancer, clusterin’s overexpression makes it a potential biomarker for various cancer types, though more research is needed to determine its precise diagnostic value. Its role in conferring resistance to cancer therapies also positions it as a promising therapeutic target. Researchers are developing strategies to modulate clusterin’s activity, such as using antisense oligonucleotides like Custirsen (OGX-011), which inhibits clusterin expression to enhance chemotherapy effectiveness and improve patient survival in various cancers.