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Progranulin, lysosomal regulation and neurodegenerative disease

Nature Reviews Neuroscience volume 18, pages 325–333 (2017)Cite this article

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Abstract

The discovery that heterozygous and homozygous mutations in the gene encoding progranulin are causally linked to frontotemporal dementia and lysosomal storage disease, respectively, reveals previously unrecognized roles of the progranulin protein in regulating lysosome biogenesis and function. Given the importance of lysosomes in cellular homeostasis, it is not surprising that progranulin deficiency has pleiotropic effects on neural circuit development and maintenance, stress response, innate immunity and ageing. This Progress article reviews recent advances in progranulin biology emphasizing its roles in lysosomal function and brain innate immunity, and outlines future avenues of investigation that may lead to new therapeutic approaches for neurodegeneration.

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Figure 1: Evolutionary dynamics of granulin domains and progranulin genes.
Figure 2: Intracellular trafficking of progranulin and its role in lysosome biogenesis and function.
Figure 3: Progranulin deficiency disrupts glia–neuron homeostasis and promotes neurodegeneration during ageing.

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Acknowledgements

The authors thank W. W. Seeley, E. H. Bigio and I. R. Mackenzie for sharing the neuropathology findings in patients with frontotemporal lobar degeneration with mutations in the gene encoding progranulin. This work has been supported by US Public Health Service grants NS095257 (A.W.K.) and NS098516 (E.J.H.), the Tau Consortium (A.W.K.), the Consortium for Frontotemporal Dementia Research (E.J.H.), VA Merit Award BX002978 (E.J.H.), and the Glenn Foundation for Medical Research (A.M., P.P.S. and A.B.)

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  1. Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, San Francisco, 94158, California, USA

    Aimee W. Kao

  2. Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, 94305, California, USA

    Andrew McKay, Param Priya Singh & Anne Brunet

  3. Department of Pathology, University of California San Francisco and Pathology Service 113B, San Francisco VA Medical Center, 513 Parnassus Avenue, San Francisco, 94143, California, USA

    Eric J. Huang

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Glossary

Deficiency

A nonspecific term used to describe both null and heterozygous loss-of-function alleles.

Frontotemporal dementia

(FTD). A clinical term describing a group of disorders caused by progressive neuron loss in the frontal and/or temporal lobes of the brain. Symptoms typically manifest as personality, behaviour and language changes and can be accompanied by motor features (for additional details, see Box 2).

Frontotemporal lobar degeneration

(FTLD). Umbrella term for a group of neurodegenerative conditions that affect primarily, or first, the frontal and/or temporal lobes of the brain, and that are characterized by a diverse array of neuronal inclusions comprising tau, TAR DNA-binding protein 43 or FUS.

Granulin

An approximately 60 amino-acid motif characterized by highly conserved cysteines that are arranged singly or in pairs, which form six disulfide bonds.

Haploinsufficiency

A loss-of-function mutation in one gene allele.

Innate immunity

A relatively nonspecific part of the immune response, consists of physical barriers (such as skin and mucosa), phagocytic cells (microglia, macrophages, dendritic cells, and so on) and circulating factors (tumour necrosis factor, interferon and complement) that co-ordinately provide protection from invading pathogens, and participate in repair and maintenance of cells and organ systems.

Lysosomal storage disease

A group of approximately 50 metabolic disorders that result from defective lysosomal degradation of cellular constituents, primarily affecting terminally differentiated neurons. Symptoms include seizure, blindness and developmental delay.

Lysosome

A subcellular organelle found in eukaryotes containing cathepsins and other acid hydrolases that are responsible for degrading and recycling cellular constituents.

Microglia

A type of non-neuronal support cells found in the CNS. Considered the resident macrophages of the brain and spinal cord, microglia are part of the innate immune system and originate from yolk sac progenitors.

Neuronal ceroid lipofuscinosis

(NCL). A relatively rare subset of lysosomal storage diseases in which protein–lipid adducts known as lipofuscin accumulate in various tissues. Symptoms include blindness, epilepsy and cognitive decline.

Nonsense mediated decay

A process that induces degradation of mRNAs that contain premature translation-termination codons, and constitutes an mRNA-surveillance mechanism that prevents the synthesis of truncated, potentially toxic, proteins.

Null

A situation in which both alleles of a gene are mutated, leading to complete loss of gene expression.

Overexpression

Excessive expression of a gene beyond the normal biologically defined levels. It can be found in pathological conditions such as cancer or it can be induced as part of experimental manipulation of a gene.

Progranulin

Also known as proepithelin, granulin-epithelin precursor, acrogranin, PC cell-derived growth factor and epithelial transforming growth factor, this precursor protein has pleotropic effects in neurons owing to its effects on lysosomal function.

Proteostasis

A linguistic blend of 'protein' and 'homeostasis' that refers to the cellular processes regulating the production, folding, trafficking and degradation of proteins.

TAR DNA-binding protein 43

(TDP43). The protein encoded by the TARDBP gene. TDP43 acts as a transcriptional regulator that shuttles between the nucleus and the cytoplasm. In certain forms of frontotemporal lobar degeneration, including those due to mutations in the genes encoding progranulin and C9ORF72, it forms intra-cytoplasmic aggregates of hyperphosphorylated, cleaved proteins.

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Kao, A., McKay, A., Singh, P. et al. Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci 18, 325–333 (2017). https://doi.org/10.1038/nrn.2017.36

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