Ceroid-lipofuscinosis neuronal protein 8 (CLN8)

Ceroid-lipofuscinosis neuronal protein 8 (CLN8) is an endoplasmic reticulum (ER)-resident transmembrane protein that serves as a critical cargo receptor for the transport of soluble lysosomal enzymes from the ER to the Golgi apparatus [1, 2]. It functions as part of the EGRESS complex, alongside CLN6, to recruit newly synthesized enzymes and facilitate their exit from the ER via COPII-coated vesicles [2, 6]. Beyond its role in protein trafficking, CLN8 has been identified as a GPG acyltransferase essential for the synthesis of bis(monoacylglycero)phosphate (BMP), a phospholipid required for lysosomal lipid homeostasis and membrane catabolism [32]. Mutations in the CLN8 gene lead to Neuronal Ceroid Lipofuscinosis type 8 (CLN8 disease), a neurodegenerative lysosomal storage disorder characterized by progressive epilepsy, vision loss, and cognitive decline [10, 14]. Therapeutic development is primarily focused on AAV-mediated gene therapy to restore functional CLN8 expression, as well as small molecule chaperones and modulators of downstream signaling pathways like PP2A [8, 15, 23]. Additionally, the CLN8 pathway is a potential target in cancer research, as upregulated lysosomal biogenesis often supports tumor growth and therapeutic resistance [1, 27].

Other names

CLN8Ceroid-lipofuscinosis neuronal 8EPMRC8orf61EGRESS complex (ER-to-Golgi relaying of enzymes of the lysosomal system)CLN8-mediated lysosomal enzyme trafficking pathway

Gene replacement therapy aims to restore functional CLN8 protein expression to normalize lysosomal enzyme trafficking and lipid metabolism [8, 23]. Pharmacological chaperones such as ambroxol and ibudilast are being explored to stabilize misfolded mutant CLN8 proteins [20]. Substrate reduction therapy (e.g., Miglustat) and modulation of downstream signaling pathways like PP2A or AMPA receptors are also investigated to mitigate pathological accumulation and excitotoxicity [15, 20, 21].