Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice.

Yoshinori Tanaka,Takashi Matsuwaki,James K Chambers,Masugi Nishihara,Keitaro Yamanouchi

doi:10.1186/s40478-014-0078-x

Yoshinori Tanaka, Takashi Matsuwaki + Show 3 more

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https://doi.org/10.1186/s40478-014-0078-x

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Abstract

IntroductionIt has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10- and 90-week-old wild-type and PGRN-deficient mice.ResultsWe showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-α and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice.ConclusionsThe present study shows that aged PGRN-deficient mice present with NCL-like pathology as well as TDP-43 aggregates in the VPM/VPL, where a particular vulnerability has been reported in NCL model mice. The present results also suggest that these pathological changes in the VPM/VPL are likely a result of lysosomal dysfunction. How PGRN prevents lysosomal dysfunction with aging remains to be elucidated.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0078-x) contains supplementary material, which is available to authorized users.

Highlights

It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease
High-power images revealed that ionized calcium-binding adapter-1 (Iba1)-IR cells in 10-week-old mice were characterized by a small soma and numerous thin, branched processes, whereas those in 90-week-old mice had a larger soma with fewer and shorter processes in both WT and KO mice (Figure 1A), suggesting that microglia were activated with aging
CD68IR cells in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL) in PGRN-deficient mice were round or amoeboid cells (Figure 2B). These results suggest that PGRN deficiency enhances CD68 expression in activated microglia in both the cerebral cortex and VPM/VPL of the aged brain, microgliosis with aging was more prominent in the VPM/VPL

Summary

Introduction

It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Haploinsufficiency of PGRN is one of the major factors causing frontotemporal lobar degeneration (FTLD) [5,6], which is characterized by ubiquitinated cytoplasmic inclusions containing TAR DNA binding protein 43 (TDP-43) [7]. The expression of cytotoxic factors is increased in relation to increased lysosomal biogenesis, and neuronal damage is exacerbated in PGRN-deficient mice [9]. Because microglial activation characterized by morphologic and phenotypic changes occurs with aging [10], increased lysosomal biogenesis and cytotoxic factor production may occur with aging in activated microglia in PGRN-deficient mice. Wils et al suggested that PGRN-deficient mice have a disrupted autophagy-lysosomal pathway with alterations in lysosomal homeostasis [11]

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