Accumulation of multiple neurodegenerative disease-related proteins in familial frontotemporal lobar degeneration associated with granulin mutation

Masato Hosokawa,Haruhiko Akiyama,Hiromi Kondo,Masato Hasegawa,Andrew C Robinson,David M Mann,Thomas G Beach,Tetsuaki Arai,Geidy E Serrano

doi:10.1038/s41598-017-01587-6

Abstract

In 2006, mutations in the granulin gene were identified in patients with familial Frontotemporal Lobar Degeneration. Granulin transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin protein. Granulin mutations were initially found in tau-negative patients, though recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease and corticobasal degeneration. Moreover, a reduction in progranulin in tau transgenic mice is associated with increasing tau accumulation. To investigate the influence of a decline in progranulin protein on other forms of neurodegenerative-related protein accumulation, human granulin mutation cases were investigated by histochemical and biochemical analyses. Results showed a neuronal and glial tau accumulation in granulin mutation cases. Tau staining revealed neuronal pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated α-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau was present in the sarkosyl-insoluble fraction, and composed of three- and four-repeat tau isoforms, resembling Alzheimer’s disease. Our data suggest that progranulin reduction might be the cause of multiple proteinopathies due to the accelerating accumulation of abnormal proteins including TDP-43 proteinopathy, tauopathy and α-synucleinopathy.

Highlights

Progranulin (PGRN) is a growth factor encoded by a single gene on chromosome 17q21, extremely close to the MAPT gene
Tau pathology, in addition to TAR-DNA binding protein of 43 kDa (TDP-43) pathology, was found in most members of two families harboring a GRN mutation[27]. These findings suggest that a decline in, or dysfunction of, PGRN may cause tau abnormalities, leading to the formation of tau pathology by activation of cyclin-dependent kinases in a P301L tau/GRN +/− mouse model[28]
All thirteen GRN mutation cases were categorized as “Type A” according to the classification system of Mackenzie et al.[32], consistent with that type of TDP-43 pathology previously reported in GRN mutation cases (Tables 2 and 3)

Summary

Introduction

Progranulin (PGRN) is a growth factor encoded by a single gene on chromosome 17q21, extremely close to the MAPT (tau) gene. Tau pathology, in addition to TAR-DNA binding protein of 43 kDa (TDP-43) pathology, was found in most members of two families harboring a GRN mutation[27] These findings suggest that a decline in, or dysfunction of, PGRN may cause tau abnormalities, leading to the formation of tau pathology by activation of cyclin-dependent kinases in a P301L tau/GRN +/− mouse model[28]. To explore these issues, we performed immunohistochemical staining and biochemical analyses on human familial GRN mutation cases and examined whether GRN reduction accelerates the accumulation of neurodegenerative-related proteins other than TDP-43. Our results suggest that at least some cases with GRN mutations may show a hitherto unrecognized accelerated pathological accumulation of tau and α-synuclein

Methods

Results

Conclusion