bp(GO:"clathrin-dependent endocytosis")

Entity

Name

clathrin-dependent endocytosis

Namespace

go

Namespace Version

20181221

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/73688d6dc24e309fca59a1340dc9ee971e9f3baa/external/go-names.belns

In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appea rs that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171]. PubMed:26751493

Phosphatidylinositol binding clathrin assembly protein, PICALM (aka CALM) assembles adaptor protein-2 (AP-2) to clathrin, thus participating in clathrin-mediated endocytosis. We have previously reported that the level of full-length PICALM is decreased in AD brains; PICALM was co-localised with phosphorylated tau in NFTs and in granulovacuolar degenerations (GVDs) in the brains of AD patients and of individuals with Down syndrome but was not observed in amyloid plaques (Ando et al., 2013). PubMed:27260836

A recent line of work revealed Aβ-promoting function of PICALM by demonstrating that PICALM depletion decreased Aβ generation through disrupting clathrin-mediated endocytosis and internalization of γ-secretase [99,100]. PubMed:29758300

However, CME was substantially reduced in cells con- taining Q82 aggregates (Fig. 1 B , arrows), with quantification of internalized transferrin fluorescence showing a 63 ± 11% reduction in aggregate-containing cells compared with cells expressing soluble Q19 or Q82 (Fig. 1 C ). PubMed:24706768

CME inhibition was also observed in cells containing aggregated forms of polyQ- expanded Htt exon 1 (Htt Q53); these cells exhibited 50 ± 15% reduced levels of internalized transferrin compared with cells with soluble Htt Q23 or Htt Q53 protein (Fig. S2 A–C ). PubMed:24706768

In contrast, there was a marked reduction in CME in neurons containing mutant Htt exon 1 Q73-CFP aggregates compared with nonexpressing cells (Fig. 5 B , Center ; quantification in Fig. 5 D ); PubMed:24706768

Nevertheless, HSC70-ag- gregate colocalization reliably predicted CME inhibition. PubMed:24706768

Importantly, aggregate-driven CME inhibition is reversible and can be rescued by nominally increasing HSC70 levels. PubMed:24706768

Although internalized transferrin levels remained un- changed in cells with near-normal amounts of HSC70, cells with over a 50% reduction in HSC70 expression had significant CME inhibition (compare Fig. 2 E and D ), with a 51 ± 17% decrease in internalized transferrin fluorescence compared with nondepleted cells. PubMed:24706768

Down- regulation of CME was not limited to polyQ-induced aggre- gation; cells with aggregated mutant SOD1 A4V also exhibited a 50 ± 10% decrease in levels of internalized transferrin com- pared with cells expressing the soluble WT or mutant protein (Fig. 1 E–G ). PubMed:24706768

Here, we show that diverse disease-associated aggregates se- quester the highly abundant major chaperone heat shock cognate protein 70 (HSC70) to the point of functional collapse of an essential cellular process, clathrin-mediated endocytosis (CME). PubMed:24706768

Moreover, internalization of APP from the cell surface for endosomal/lysosomal degradation can be mediated by clathrin PubMed:21214928

In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appea rs that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171]. PubMed:26751493

Phosphatidylinositol binding clathrin assembly protein, PICALM (aka CALM) assembles adaptor protein-2 (AP-2) to clathrin, thus participating in clathrin-mediated endocytosis. We have previously reported that the level of full-length PICALM is decreased in AD brains; PICALM was co-localised with phosphorylated tau in NFTs and in granulovacuolar degenerations (GVDs) in the brains of AD patients and of individuals with Down syndrome but was not observed in amyloid plaques (Ando et al., 2013). PubMed:27260836