Abstract
GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration.
Highlights
Progranulin is widely expressed in epithelia, bone marrow, immune cells, solid organs, and the nervous system both during development and in adulthood (1–5)
Progranulin is evolutionarily conserved in Animalia: homologs exist in vertebrates and Caenorhabditis elegans (14), but seemingly not in Drosophila
Biological activities attributed to progranulin are numerous; the protein is made up of several granulin domains, which can be individually liberated by neutrophil proteases
Summary
Two homozygous GRN-deficient patients have been recently reported (30). These patients presented with adult onset neuronal ceroid lipofuscinosis (NCL), suffering from progressive loss of vision, retinal dystrophy, cerebellar ataxia, and seizures (Table 1). NCLs are genetic progressive lysosomal storage diseases characterized by accumulation of lipofuscin (31). At least 10 related disorders are classified as NCLs. Causative muta-
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