The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases

Abstract

Although different neurodegenerative diseases are defined by distinct pathological proteins, they share many common features including protein aggregation. Despite this commonality, most current therapeutic approaches in the field, such as anti-aggregate antibodies, are focused on individual diseases or single neuropathologies with only limited success. The endolysosomal proteins progranulin and TMEM106B were both initially associated with frontotemporal lobar degeneration but have subsequently also been linked to other neurodegenerative diseases. Thus, these proteins are predicted to participate in common pathogenic pathways shared across various neurodegenerative diseases. Importantly, recent discoveries of TMEM106B amyloid fibrils in varied neurodegenerative diseases and glycosphingolipid regulation by progranulin and TMEM106B further support their central roles in cross-disease neurodegenerative mechanisms. This review summarizes recent advances in progranulin and TMEM106B function within the endolysosomal system and neurodegenerative diseases. It describes preclinical models and therapeutic approaches for progranulin- and TMEM106B-associated diseases. We also discuss future direction leading to novel alternative therapies targeting shared mechanisms in neurodegenerative diseases.

Keywords: Aging; Alzheimer’s disease; Amyloid fibrils; Endolysosome; Frontotemporal Lobar degeneration; GBA1; Glycosphingolipid; Parkinson’s disease; Progranulin; TMEM106B.

Fig. 1

Schematic illustration of structure and cellular uptake of PGRN. a, PGRN-associated neurodegenerative diseases. Haploinsufficiency (~50% loss) of PGRN causes FTLD, the second most common cause of dementia in people under the age of 65, while complete loss of PGRN causes the lysosomal storage disorder CLN11 with the age of onset of ~15 years, although rare homozygous GRN mutations were reported to cause FTLD with the age of onset of ~50 years. In addition, several GRN variants increase risk for AD and PD, which usually develop after age 65 and 60, respectively. A GRN variant is reported to cause 10-20% reduction in PGRN levels. Furthermore, heterozygous GRN mutations have been found in a substantial number of AD and PD patients. b, Schematic representation of PGRN. Human PGRN is a highly glycosylated protein composed of 7.5 cysteine-rich granulin domains (A to G and P) that are connected by short linker regions. P represents paragranulin. Amino acids 1 to 17 are the signal sequence. Granulins numbered 1 through 7 are based on the UniProtKB database: P28799. c, Schematic illustration of lysosomal delivery of PGRN and PSAP via their receptors. Extracellular PGRN binds to cell surface sortilin receptor through its C-terminal tail and is delivered to lysosomes, where PGRN is processed into granulins by cathepsins and AEP. PGRN also binds to PSAP extracellularly through the linker region between saposins B and C and can be delivered to lysosomes via the PSAP receptors M6PR and LRP1. The PGRN-PSAP complex may also be important to facilitate lysosomal delivery of extracellular PSAP via sortilin. In the lysosome, PSAP is processed into saposins, which are involved in glycosphingolipid degradation. Figure was created with BioRender.com.

Fig. 2

Schematic illustration of structure and amyloid formation of TMEM106B. a, TMEM106B genomic region on chromosome 7p21. Exons (1-9) are indicated by blue boxes and the coding regions are labeled in dark blue. The major SNPs associated with neurodegenerative diseases are shown with protective/minor and risk/major alleles. Multiple SNPs near and in the TMEM106B gene, including rs1990620, rs1990622, rs3173615, rs6966915, and rs1020004, are in strong LD, constituting two common TMEM106B haplotypes, one associated with increased disease risk, and the other with a protective effect. AluYb8 insertion is found in 3’ UTR of the TMEM106B risk haplotype. b, Schematic representation of TMEM106B. The 274-amino acid human TMEM106B consists of an N-terminal intrinsically disordered cytoplasmic region, a single-pass transmembrane region, and a C-terminal luminal region with five glycosylation sites (N145, N151, N164, N183, and N256). T185S and D252N amino acid substitutions associated with FTLD and HLD are indicated. c, Amyloid fibril formation of CTF of TMEM106B. TMEM106B forms homodimers and undergoes shedding and C-terminal trimming by unknown lysosomal enzyme(s). It is currently unknown whether dimerization affects the processing of TMEM106B and what protease(s) mediate the processing to form the fibrils. A precise cleavage between resides 119 and 120 appears to be required for the amyloid fibril formation because Ser120 is buried in the fibril core, leaving no space for the other N-terminal residues. Upon fibrillization, the luminal region of TMEM106B undergoes a conformational change from a structure with a ubiquitous 7-bladed β sandwich fold (PDB: 8B7D) to ones with a five-layered fold consisting of 17-19 β-strands (PDB: 7QVC). The fibril formation is age-dependent and may be promoted by the TMEM106B risk haplotype, GRN mutation, or under LATE-NC condition. Note that, for the sake of simplicity, glycosylation is omitted from the illustration but the glycosylation sites within the fibril core (N145, N151, N164, and N183) are reported to be fully glycosylated. d, In TMEM106B fibrils, three major filament folds (I-III) and two doublet polymorphisms (1,2) have been reported. Unlike other amyloid proteins, no clear relationships between the filament folds and diseases were found. Folds I-III and doublets 1-2 are extracted from PDB: 7QVC, 7QWG, 7QWM, 7QVF, and 7SAS, respectively.Figure was created with BioRender.com.

Fig. 3

Glycosphingolipid regulation by PGRN and TMEM106B. PGRN and/or granulins bind to GCase and HexA and promote their activity to limit accumulation of GlcCer (and GlcSph) and gangliosides in lysosomes. PGRN also binds and stabilizes anionic phospholipid BMP, which stimulates GCase activity and ganglioside degradation at the intraluminal vesicles of lysosomes. Granulins may also bind and stabilize BMP, although it has not been proven. TMEM106B binds to GALC and regulates its activity to maintain GalCer levels in lysosomes. PSAP is cleaved into saposins A to D in lysosomes and saposins A and C are known to stimulate GALC and GCase activity, respectively. Figure was created with BioRender.com