Progranulin burst on the scene of neurodegenerative disease as a major genetic cause of frontotemporal dementia (FTD) in 2006, only months before TDP-43 was identified as the main protein constituent of the histopathological lesions in the same patients. Up to that point, the only known FTD gene had been MAPT, located near the progranulin gene, GRN, on chromosome 17q21, and the twin discoveries broke a double logjam in the field. The roughly 70 GRN mutations known to date explain all 17q21-linked autosomal-dominant FTD families not accounted for by tau mutations, and because all FTD patients with a GRN mutation have TDP-43 pathology, TDP-43 explains these family’s tau-negative protein inclusions. GRN mutations explain up to 20 percent of familial and 5 percent of sporadic FTD. Histopathological commonalities notwithstanding, GRN mutations lead to a variety of clinical presentations, causing mostly behavioral FTD and progressive nonfluent aphasia, but also rare presentations of Alzheimer’s disease or parkinsonism. 

All pathologic GRN mutations reduce progranulin levels or result in loss of function. Indeed, blood progranulin levels indicate the presence of a pathogenic progranulin mutation and are rapidly becoming a diagnostic biomarker. Progranulin is a secreted growth factor known for its role in biological processes such as inflammation, wound healing, and cancer, and for its neurotrophic properties. It is proteolytically processed into peptides called granulins, which are poorly understood. Progranulin’s role in FTD is being investigated in parallel with potential therapeutic approaches aimed at increasing its levels in the CNS.

Several factors are known to influence progranulin expression. They include intrinsic factors, for example the gene TMEM106B and various microRNAs, as well as pharmacological agents, such as the histone deacetylase inhibitor SAHA and certain alkalizing drugs. Agents targeting the endocytic progranulin receptor sortilin-1 appear to increase plasma progranulin levels by slowing its internalization. Homozygous GRN mutations cause the rare lysosomal storage disease ceroid lipofuscinosis, and progranulin localizes to intraneuronal membrane compartments, including lysosomes. Both homozygous and heterozygous GRN knockout mice exist; the former show both behavioral and inflammatory phenotypes, the latter develop only the former.

References

Alzpedia Citations

1. TDP-43
2. Tau (MAPT)

Further Reading