2021年8月3日 · In contrast, over-expression of CTSL, which digests PGRN in vitro but was not shown to release Gran F, led to a significant decrease in full-length PGRN without an increase granulin F (Fig. 3f-h). This suggests that in cells, both AEP and CTSL can cleave full length PGRN but only AEP liberates granulin F.

2018年5月9日 · Upon reaching the lysosome, PGRN can be cleaved by CTSL into individual granulin peptides and PSAP cleaved by CTSD into individual saposins. PGRN/granulin E can then bind to CTSD to help stabilize it and/or augment its activity

2024年6月5日 · This strategy combines a TfR-mediated, brain-penetrant PGRN biologic with AAV-targeted delivery to the liver, enabling brain-wide PGRN delivery with a single peripheral administration treatment paradigm without requiring direct CNS injection.

In neurons, PGRN co-localizes with cathepsin D (CTSD), an aspartyl protease degrading protein present in the lysosomes (Beel et al., 2017), and increases the activity of CTSD but not that of cathepsin B (CTSB) or CTSL (Valdez et al., 2017). PGRN also stimulates the maturation of the CTSD precursor (proCTSD) at an acidic pH (Butler et al., 2019).

2017年1月10日 · CTSL-I and CTSS-I led to increased levels of CTSD mat both in mock and PGRN-transfected cells, whereas CA074Me partially increased CTSD mat only in PGRN-transfected cells (Fig. 8B and C). Moreover, CTSD mat degradation was inhibited in cells transfected with PGRN and exposed to CA074Me for 3 …

2022年1月4日 · Here, we report that sortilin and prosaposin independently regulate lysosomal trafficking of progranulin in vivo. The deletion of either prosaposin or sortilin alone results in a significant decrease in the ratio of granulin peptides versus full-length progranulin in …

2021年8月1日 · Brain tissue from individuals with FTLD-TDP-Pgrn showed increased PGRN processing to granulin F and increased AEP activity in degenerating brain regions but not in regions unaffected by disease.

Homozygous or heterozygous mutations in the GRN gene, encoding progranulin (PGRN), cause neuronal ceroid lipofuscinosis (NCL) or frontotemporal dementia (FTD), respectively. NCL and FTD are characterized by lysosome dysfunction and neurodegeneration, indicating PGRN is important for lysosome homeostasis in the brain.

2017年8月18日 · PGRN can be cleaved into seven 6-kDa proteins called granulins (GRNs); however, little is known about how GRNs are produced or if levels of GRNs are altered in FTD-GRN mutation carriers. Here, we report the identification and characterization of antibodies that reliably detect several human GRNs by immunoblot and immunocytochemistry.

2023年11月16日 · We found that PGRN loss impairs the lysosome’s degradative capacity with increased levels of v-ATPase subunits on the lysosome membrane, increased hydrolases within the lysosome, altered protein regulations related to …