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

Xiaolai Zhou,William W Seeley,Owen Adam Brady,Lirong Sun,Nozomi Nishimura,Ji Whae Choi,Alissa L Nana,Oliver Bracko,Jean C Cruz Hernandez,Fenghua Hu,Yan Jia

doi:10.1038/ncomms15277

Xiaolai Zhou, William W Seeley + Show 9 more

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https://doi.org/10.1038/ncomms15277

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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.

Highlights

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)
In a proteomic screen searching for PGRN-binding partners[19], we uncovered a novel interaction between PGRN and PSAP, the precursor of saposin peptides (A, B, C and D) that are essential for glycosphingolipid metabolism in the lysosome[21,22,23]
Several receptors have been shown to mediate PSAP lysosomal trafficking, including the cation-independent mannose 6-phosphate receptor (M6PR)[24,25], sortilin[26] and LRP127. Since both PGRN and PSAP have been reported to bind to sortilin[18,26], we investigated whether PSAP and PGRN compete with each other for sortilin binding

Summary

Introduction

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). 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. 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. Reduction in PSAP levels leads to FTLD-like phenotypes in mice, supporting the idea that impaired lysosomal trafficking of PSAP might be a shared disease mechanism in FTLD and NCL caused by GRN mutations

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