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

• DOI: 10.1186/s40478-014-0078-x
• Publication Date: 2014-07-14T14:12:06Z
• Authors: Yoshinori Tanaka; James K Chambers; Takashi Matsuwaki; Keitaro Yamanouchi; Masugi Nishihara
• Keywords: Sequestosome 1; Frontotemporal lobar degeneration; Astrogliosis; Neuronal ceroid lipofuscinosis; Lipofuscin

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. Previous studies also suggested PGRN is involved in modulating function. To elucidate the pathophysiological role of aged brain, present study, function pathological changes brain were investigated using 10- 90-week-old wild-type PGRN-deficient mice. We showed caused enhanced CD68 expression activated microglia astrogliosis cortex thalamus, especially ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), brain. Immunoreactivity for Lamp1 (lysosome marker) VPM/VPL lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, transcription factor EB increased by deficiency. Aggregates p62, which selectively degraded autophagy-lysosomal system, observed glial cells TAR DNA binding protein 43 (TDP-43) aggregates cytoplasm neurons cell-derived cytotoxic factors macrophage expressed gene 1, cytochrome b-245 light chain, heavy complement C4, tumor necrosis factor-α lipocalin 2. In addition, loss disrupted myelination cerebral The study shows mice with NCL-like pathology well TDP-43 VPM/VPL, where particular vulnerability reported NCL model results suggest these are likely result dysfunction. How prevents dysfunction aging remains to be elucidated.