The Role of Ceroid Lipofuscinosis Neuronal Protein 5 (CLN5) in Endosomal Sorting

Abstract

cMutations in the gene encoding CLN5 are the cause of Finnish variant late infantile Neuronal Ceroid Lipofuscinosis (NCL), and the gene encoding CLN5 is 1 of 10 genes (encoding CLN1 to CLN9 and cathepsin D) whose germ line mutations result in a group of recessive disorders of childhood. Although CLN5 localizes to the lysosomal compartment, its function remains unknown. We have uncovered an interaction between CLN5 and sortilin, the lysosomal sorting receptor. However, CLN5, unlike prosaposin, does not require sortilin to localize to the lysosomal compartment. We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). In addition, we show that the retromer recruitment machinery is also affected by CLN5 depletion, as we found less loaded Rab7, which is required to recruit retromer. Taken together, our results support a role for CLN5 in controlling the itinerary of the lysosomal sorting receptors by regulating retromer recruitment at the endosome.

The retromer complex – endosomal protein recycling and beyond

“…Recent evidence has linked the activity of the ceroidlipofuscinosis neuronal 5 (CLN5) protein to the regulation of the recruitment of the cargo-selective complex through Rab7a (Mamo et al, 2012). CLN5 is mutated in Batten disease, a lysosomal storage disorder, and has been shown to bind to the sortilin protein, a known cargo for retromer (Seaman, 2004;Seaman, 2007;Canuel et al, 2008).…”

“…CLN5 is mutated in Batten disease, a lysosomal storage disorder, and has been shown to bind to the sortilin protein, a known cargo for retromer (Seaman, 2004;Seaman, 2007;Canuel et al, 2008). Loss of CLN5 expression results in reduced levels of active Rab7a and compromised retromer recruitment, and leads to degradation of sortilin and CIMPR (Mamo et al, 2012). Unlike Rab7a, CLN5 does not appear to be conserved across all eukaryotes and, therefore, simpler organisms (e.g.…”

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

“…Retromer-related dysfunctions have been reported not only in neurological disorders such as Down syndrome [29,30], hereditary spastic paraplegia [31], cerebral lipofuscinosis [32], prionopathy [33], and Nieman Pick type C1 disease [34], but have also been linked to non-neurological disorders such as type II diabetes [35,36], osteoporosis [37], retinal degeneration [38], and Legionella disease [39] (see Table 1). Several of these diseases have a clear pathological molecular link to retromer; in other cases, the connection is less clear and more tangential.…”

Neuronal Ceroid Lipofuscinosis: Impact of Recent Genetic Advances and Expansion of the Clinicopathologic Spectrum

“…Intriguingly, progranulin has also been demonstrated to bind sortilin, which is thought to direct its trafficking into the endosomal-lysosomal system [40]. It is noteworthy that interactions between other NCL-related proteins and sortilin and/or its retrograde trafficking receptor, retromer, have also been demonstrated [41-43, 28], highlighting further commonalities among at least several forms of NCL (Figure 1). The potential overlap in disease pathophysiology between GRN -associated NCL and FTLD raised by these new genetic data will be further discussed in the next section of this review.…”