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

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 pro...

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Published in:Nature communications 2017-05, Vol.8 (1), p.15277-15277, Article 15277
Main Authors: Zhou, Xiaolai, Sun, Lirong, Bracko, Oliver, Choi, Ji Whae, Jia, Yan, Nana, Alissa L., Brady, Owen Adam, Hernandez, Jean C. Cruz, Nishimura, Nozomi, Seeley, William W., Hu, Fenghua
Format: Article
Language:English
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Alzheimer's disease
Disease
Genes
Glycoproteins
Humanities and Social Sciences
Molecular biology
multidisciplinary
Mutation
Neurosciences
Pathology
Peptides
Science
Science (multidisciplinary)
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Summary: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. Mutations in the granulin gene are associated with frontotemporal lobe dementia (FTLD) and a lysosomal storage disease. The authors show that reduced progranulin levels leads to impaired neuronal uptake and lysosomal delivery of prosaposin, and that decreased prosaposin expression in mice leads to FTLD-like behaviour.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms15277