Box 1.

Key outstanding questions regarding PGRN and TMEM106B in the field

What are functions of individual granulin peptides versus PGRN in the brain?

How do TMEM106B variants affect FTLD-GRN and other neurodegenerative diseases?

Do PGRN and TMEM106B exert their deleterious/protective effects predominantly in neurons versus glia?

What are the mechanisms of amyloid fibril formation of C-terminal fragments of TMEM106B?

Do the TMEM106B fibrils directly contribute to pathophysiology of neurodegenerative diseases?

Can we establish a preclinical model that fully reproduces effects of PGRN haploinsufficiency?

What are the mechanisms by which PGRN deficiency causes alteration in lipids such as BMP and glycosphingolipids?

Is the lipid alteration caused by PGRN or TMEM106B deficiency directly responsible for PGRN- or TMEM106B-associated neurological diseases?

Do PGRN-boosting therapies have side effects?