Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations

Abstract

Haploinsufficiency of progranulin (PGRN) due to mutations in the granulin (GRN) gene causes frontotemporal lobar degeneration (FTLD), and complete loss of PGRN leads to a lysosomal storage disorder, neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests that PGRN is essential for proper lysosomal function, but the precise mechanisms involved are not known. Here, we show that PGRN facilitates neuronal uptake and lysosomal delivery of prosaposin (PSAP), the precursor of saposin peptides that are essential for lysosomal glycosphingolipid degradation. We found reduced levels of PSAP in neurons both in mice deficient in PGRN and in human samples from FTLD patients due to GRN mutations. Furthermore, mice with reduced PSAP expression demonstrated FTLD-like pathology and behavioural changes. Thus, our data demonstrate a role of PGRN in PSAP lysosomal trafficking and suggest that impaired lysosomal trafficking of PSAP is an underlying disease mechanism for NCL and FTLD due to GRN mutations.

The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C

“…This will be of therapeutic interest for FTLD, since haploinsufficiency of PGRN is a leading cause of FTLD and impaired PSAP lysosomal trafficking is observed in FTLD patients with GRN mutations (Zhou et al . ).…”

“…Our previous studies have shown that PGRN and PSAP form a complex, both intracellularly and extracellularly, and facilitate each other's lysosomal delivery (Zhou et al . , ). Since both PGRN and PSAP are essential for proper lysosomal function and loss of function in either gene causes lysosomal storage diseases, more studies on the interaction of PGRN and PSAP will help us develop strategies to enhance the binding affinity between these two proteins and thus the activities of PGRN and PSAP.…”

“…The physical interaction of PGRN and PSAP not only facilitates PGRN lysosomal trafficking but also PSAP trafficking, as we have recently shown that PGRN bridges the interaction between PSAP and sortilin to facilitate PSAP uptake and lysosomal delivery in neurons (Zhou et al . ). Furthermore, PGRN haploinsufficiency in FTLD patients impairs PSAP lysosomal trafficking and decreases neuronal saposin level (Zhou et al .…”

“…Furthermore, PGRN haploinsufficiency in FTLD patients impairs PSAP lysosomal trafficking and decreases neuronal saposin level (Zhou et al . ). Thus, PGRN and PSAP facilitate each other's lysosomal trafficking, and PGRN‐PSAP interaction is important for maintaining proper lysosomal function in the aged brain.…”

Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

“…PGRN is a growth factor‐like protein with neurotrophic properties in the brain (Van Damme et al , ). PGRN is also transported to lysosomes (Hu et al , ; Zhou et al , ) where it appears to regulate expression and activity of lysosomal proteins (Ahmed et al , ; Hu et al , ; Wils et al , ; Tanaka et al , ,b; Gotzl et al , , , ; Beel et al , ; Chang et al , ; Ward et al , ; Zhou et al , ). PGRN is proteolytically processed into granulin peptides, which can be found in biological fluids (Bateman et al , ; Shoyab et al , ; Belcourt et al , ; Cenik et al , ).…”