Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

Abstract

Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.

Progranulin, lysosomal regulation and neurodegenerative disease

“…In support of this idea, neurons in G rn −/− mice show pathological features similar to those seen in NCL 44–47 . Similar lysosomal phenotypes have also been detected in patients with FTLD with GRN mutations 41,42 . Future studies are required to determine whether simultaneous losses of progranulin in microglia, astrocytes and neurons have synergistic effects to promote neurodegeneration (FIG.…”

“…Skin biopsy reveals lipofuscin accumulation in a vacuole-like organelle, confirming the NCL diagnosis. Interestingly, several studies show that cortical neurons and lymphoblasts from patients with FTLD with GRN mutations also contain a marked increase in lysosomal storage materials 41,42 . Together, these results further support the gene-dosage effects of progranulin deficiency in neurodegeneration.…”

Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice

“…A recent study has also reported increased lipofuscin in heterozygous GRN mutation carriers (Ward et al, 2017). The molecular mechanisms underlying increased lipofuscin accumulation by PGRN deficiency are currently unknown.…”

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia

“…Heterozygous GRN pathogenic variants cause about 10% of all FTD cases, while homozygous recessive pathogenic variants in GRN have been linked to recessive adult-onset NCL in two separate families [3, 6, 7, 11, 69, 79]. More recently, Ward and colleagues provided further evidence for phenotypic overlap between FTLD and NCL due to pathogenic GRN variants by identifying NCL-like biological hallmarks in haploinsufficient GRN patients [75]. Given the relationship of GRN to NCL, rare variation in other NCL genes, including CTSF, has also been suggested to contribute risk to FTD [80].…”