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Granulin mutations causing progranulin reduction may accelerate the intracellular accumulation of neurodegenerative-related proteins other than TDP-43 in the brains of familial frontotemporal lobar degeneration patients with granulin mutations - the pathologies seen in GRN mutation cases may possibly be renamed “neuronoglial multiple proteinopathies”

＜Journal＞

Scientific Reports, 7(1): 1513, 2017 May 4
doi: 10.1038/s41598-017-01587-6.

＜Authors＞

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

＜Title＞

Accumulation of multiple neurodegenerative disease-related proteins in familial frontotemporal lobar degeneration associated with granulin mutation
https://www.nature.com/articles/s41598-017-01587-6

1. Background

Mutations in the granulin gene were identified in patients with familial Frontotemporal Lobar Degeneration in 2006. 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 (Hosokawa M et al, Journal of Neuropathology and Experimental Neurology 74: 158-165, 2015). 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.

2. Research summary

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.

3. Conclusion

The results of the present study show that GRN mutations causing PGRN reduction may accelerate the intracellular accumulation of not only TDP-43 but also tau and α-synuclein in the brains of familial FTD patients with GRN mutations. This suggests that GRN mutations causing PGRN reduction may be causative or represent risk factors for multiple proteinopathies (TDP-43, tauopathy or α-synucleinopathy). Our findings suggest that the pathologies seen in GRN mutation cases may possibly be renamed “neuronoglial multiple proteinopathies”.

This research was partially supported by a Daiwa Securities Research Foundation grant to M. Hosokawa.

＜Contact＞

Dementia Research Project, Department of Dementia and Higher Brain Function,
Tokyo Metropolitan Institute of Medical Science

Chief Researcher : Masato Hosokawa

Email : hosokawa-ms [at] igakuken.or.jp

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Dementia Research Project ▶