| CCL5 Protein (RANTES) | |
|---|---|
| Gene | [CCL5](/genes/ccl5) |
| UniProt ID | [P13501](https://www.uniprot.org/uniprot/P13501) |
| PDB Structures | 1RTN, 2L9H, 5COY |
| Molecular Weight | ~8 kDa (monomer), ~40 kDa (oligomer) |
| Subcellular Localization | Secreted, extracellular |
| Protein Family | CC chemokine family |
CCL5 Protein is a protein encoded by the CCL5 gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
CCL5 (C-C motif chemokine ligand 5), also known as RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), is a small secreted chemokine of approximately 8 kDa in its monomeric form[1]. The protein adopts the characteristic chemokine fold consisting of a flexible N-terminal loop followed by three β-strands arranged in a β-sheet, and a C-terminal α-helix[2]. The structure contains four conserved cysteine residues forming two disulfide bonds (Cys-Cys motif) that stabilize the tertiary structure. CCL5 can form higher-order oligomers through interactions involving the N-terminal region, which is important for its biological activity and for interacting with glycosaminoglycans on the cell surface[3].
CCL5 is a pro-inflammatory chemokine expressed by various cell types including T cells, macrophages, platelets, neurons, and glial cells[1:1]. In the nervous system, CCL5 plays complex roles in normal physiology and pathological processes. It acts as a chemoattractant for immune cells, recruiting monocytes, memory T cells, and eosinophils to sites of inflammation[4]. In the brain, CCL5 is produced by neurons and astrocytes and modulates synaptic transmission and plasticity. The chemokine influences microglial activation states and can regulate neurogenesis during development and in adult brains[5]. CCL5 also interacts with its receptors CCR1, CCR3, and CCR5 to signal through Gαi-coupled pathways, leading to calcium mobilization, chemotaxis, and activation of MAP kinase and PI3K pathways[6].
CCL5 is significantly upregulated in Alzheimer's disease brain tissue and cerebrospinal fluid, where it contributes to chronic neuroinflammation[7]. Elevated CCL5 levels correlate with disease progression and cognitive decline. In AD models, CCL5 promotes microglial activation and the production of other pro-inflammatory cytokines, creating a feed-forward inflammatory loop that exacerbates neuronal damage[8]. The chemokine may also affect amyloid-β processing and clearance, with some studies suggesting that CCL5 can modulate APP processing through inflammatory signaling pathways[9].
In Parkinson's disease, CCL5 is elevated in the substantia nigra and striatum of PD patients and in animal models of the disease[10]. The chemokine contributes to neuroinflammation surrounding dopaminergic neurons, recruiting peripheral immune cells into the brain parenchyma. Studies show that CCL5 can exacerbate MPTP-induced dopaminergic neurodegeneration, and blocking CCL5-CCR5 signaling provides neuroprotective effects in experimental PD models[11]. CCL5 also interacts with α-synuclein pathology, as the protein can be recruited into Lewy bodies and may influence α-synuclein aggregation[12].
CCL5 is upregulated in ALS patients and in mouse models of the disease, particularly in motor neurons, astrocytes, and microglia[13]. The chemokine contributes to the inflammatory environment surrounding motor neurons and promotes the recruitment of macrophages and T cells to the spinal cord. Elevated CCL5 in CSF of ALS patients correlates with disease progression. Experimental studies suggest that CCL5-CCR5 signaling may accelerate motor neuron degeneration through enhanced excitotoxicity and oxidative stress[14].
CCL5 plays a complex role in multiple sclerosis, being involved in both pro-inflammatory and potentially remyelination-promoting processes[15]. While it recruits inflammatory cells to demyelinating lesions, some studies suggest CCL5 may also support oligodendrocyte precursor cell migration and differentiation. The chemokine's role in MS appears context-dependent, with both pathogenic and protective functions described in different disease phases[16].
Therapeutic strategies targeting CCL5 in neurodegeneration include[17][18]:
CCL5/RANTES in Neuroinflammation and Neurodegeneration. ↩︎ ↩︎
Schall TJ, et al. RANTES is a "regulated on activation, normal T expressed and secreted" peptide. Nature. 1990. ↩︎
Liu Q, et al. Chemokine CCL5 and its receptors in the nervous system. Progress in Neurobiology. 2013. ↩︎
Murphy PM. Molecular physiology of CC chemokine receptors. Annual Review of Physiology. 1996. ↩︎
Huang DR, et al. CC chemokines and neuronal injury. Advances in Experimental Medicine and Biology. 2006. ↩︎
Jiang H, et al. CCL5 deficiency promotes neuroinflammation and cognitive impairment in Alzheimer's disease. Journal of Neuroinflammation. 2022. ↩︎
Szczepanik AM, et al. RANTES modulates amyloid-β peptide-induced inflammation in Alzheimer's disease. Journal of Neuroimmunology. 2003. ↩︎
Cheng J, et al. Elevated CCL5 levels in Parkinson's disease. Neuroscience Letters. 2018. ↩︎
Choi DY, et al. Targeting CC chemokine receptor 5 (CCR5) for Parkinson's disease therapy. Neuroscience Bulletin. 2014. ↩︎
Kim C, et al. Chemokines and their receptors in Lewy body diseases. Journal of Movement Disorders. 2018. ↩︎
Kuhle J, et al. Increased CCL5 expression in ALS. Neurology Neuroimmunology Neuroinflammation. 2015. ↩︎
Mantovani S, et al. CC chemokines in amyotrophic lateral sclerosis. Neural Regeneration Research. 2019. ↩︎
Ransohoff RM. The chemokine system in neuroinflammation. Frontiers in Bioscience. 2002. ↩︎
Omari KM, et al. RANTES contributes to the pathogenesis of multiple sclerosis. Brain. 2005. ↩︎
Miller RJ, et al. Chemokines and the pathophysiology of CNS disease. Neuron. 2008. ↩︎
Bajetto A, et al. Chemokine signaling in the brain. Neurochemical Research. 2001. ↩︎