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Y682G Mutation of Amyloid Precursor Protein Promotes Endo-Lysosomal Dysfunction by Disrupting APP-SorLA Interaction.

La Rosa LR, Perrone L, Nielsen MS, Calissano P, Andersen OM, Matrone C - Front Cell Neurosci (2015)

Bottom Line: Here, we report that Y682G mutation affects formation of the APP complex with sortilin-related receptor (SorLA), resulting in endo-lysosomal dysfunctions and neuronal degeneration.These results might open new possibilities in comprehending the role played by SorLA in its interaction with APP and in the progression of neuronal degeneration.In addition, they further underline the crucial role played by Y682 residue in controlling APP trafficking in neurons.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome , Rome , Italy.

ABSTRACT
The intracellular transport and localization of amyloid precursor protein (APP) are critical determinants of APP processing and β-amyloid peptide production, thus crucially important for the pathophysiology of Alzheimer's disease (AD). Notably, the C-terminal Y682ENPTY687 domain of APP binds to specific adaptors controlling APP trafficking and sorting in neurons. Mutation on the Y682 residue to glycine (Y682G) leads to altered APP sorting in hippocampal neurons that favors its accumulation in intracellular compartments and the release of soluble APPα. Such alterations induce premature aging and learning and cognitive deficits in APP Y682G mutant mice (APP (YG/YG) ). Here, we report that Y682G mutation affects formation of the APP complex with sortilin-related receptor (SorLA), resulting in endo-lysosomal dysfunctions and neuronal degeneration. Moreover, disruption of the APP/SorLA complex changes the trafficking pathway of SorLA, with its consequent increase in secretion outside neurons. Mutations in the SorLA gene are a prognostic factor in AD, and changes in SorLA levels in cerebrospinal fluid are predictive of AD in humans. These results might open new possibilities in comprehending the role played by SorLA in its interaction with APP and in the progression of neuronal degeneration. In addition, they further underline the crucial role played by Y682 residue in controlling APP trafficking in neurons.

No MeSH data available.


Related in: MedlinePlus

(A) In normal neurons, SorLA (green) controls APP (blue–yellow) trafficking from early endosome (EE) back to the trans-Golgi network (TGN) or plasma membrane (PM). (B) Because of the Y682G mutation on the Y682ENPTY687 domain of APP (YG), SorLA is no longer able to interact with mutated APP (blue–red); consequently, mutated APP mislocalizes to the late endosome (LE) and lysosome (LS) where it is likely processed to generate CTF peptides (Basso and Matrone, 2013). The accumulation of APP in the late endosome and lysosomes induces alterations in lysosomal activity and leads to the neuronal defects that were previously reported in APPYG/YG mice (YG) (Matrone, 2013). As a result of the lack of binding to APP, SorLA is trafficked to the plasma membrane where it is rapidly cleaved and secreted outside neurons.
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d35e1089: (A) In normal neurons, SorLA (green) controls APP (blue–yellow) trafficking from early endosome (EE) back to the trans-Golgi network (TGN) or plasma membrane (PM). (B) Because of the Y682G mutation on the Y682ENPTY687 domain of APP (YG), SorLA is no longer able to interact with mutated APP (blue–red); consequently, mutated APP mislocalizes to the late endosome (LE) and lysosome (LS) where it is likely processed to generate CTF peptides (Basso and Matrone, 2013). The accumulation of APP in the late endosome and lysosomes induces alterations in lysosomal activity and leads to the neuronal defects that were previously reported in APPYG/YG mice (YG) (Matrone, 2013). As a result of the lack of binding to APP, SorLA is trafficked to the plasma membrane where it is rapidly cleaved and secreted outside neurons.


Y682G Mutation of Amyloid Precursor Protein Promotes Endo-Lysosomal Dysfunction by Disrupting APP-SorLA Interaction.

La Rosa LR, Perrone L, Nielsen MS, Calissano P, Andersen OM, Matrone C - Front Cell Neurosci (2015)

(A) In normal neurons, SorLA (green) controls APP (blue–yellow) trafficking from early endosome (EE) back to the trans-Golgi network (TGN) or plasma membrane (PM). (B) Because of the Y682G mutation on the Y682ENPTY687 domain of APP (YG), SorLA is no longer able to interact with mutated APP (blue–red); consequently, mutated APP mislocalizes to the late endosome (LE) and lysosome (LS) where it is likely processed to generate CTF peptides (Basso and Matrone, 2013). The accumulation of APP in the late endosome and lysosomes induces alterations in lysosomal activity and leads to the neuronal defects that were previously reported in APPYG/YG mice (YG) (Matrone, 2013). As a result of the lack of binding to APP, SorLA is trafficked to the plasma membrane where it is rapidly cleaved and secreted outside neurons.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4388009&req=5

d35e1089: (A) In normal neurons, SorLA (green) controls APP (blue–yellow) trafficking from early endosome (EE) back to the trans-Golgi network (TGN) or plasma membrane (PM). (B) Because of the Y682G mutation on the Y682ENPTY687 domain of APP (YG), SorLA is no longer able to interact with mutated APP (blue–red); consequently, mutated APP mislocalizes to the late endosome (LE) and lysosome (LS) where it is likely processed to generate CTF peptides (Basso and Matrone, 2013). The accumulation of APP in the late endosome and lysosomes induces alterations in lysosomal activity and leads to the neuronal defects that were previously reported in APPYG/YG mice (YG) (Matrone, 2013). As a result of the lack of binding to APP, SorLA is trafficked to the plasma membrane where it is rapidly cleaved and secreted outside neurons.
Bottom Line: Here, we report that Y682G mutation affects formation of the APP complex with sortilin-related receptor (SorLA), resulting in endo-lysosomal dysfunctions and neuronal degeneration.These results might open new possibilities in comprehending the role played by SorLA in its interaction with APP and in the progression of neuronal degeneration.In addition, they further underline the crucial role played by Y682 residue in controlling APP trafficking in neurons.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular Biology and Neurobiology, National Council of Research of Rome , Rome , Italy.

ABSTRACT
The intracellular transport and localization of amyloid precursor protein (APP) are critical determinants of APP processing and β-amyloid peptide production, thus crucially important for the pathophysiology of Alzheimer's disease (AD). Notably, the C-terminal Y682ENPTY687 domain of APP binds to specific adaptors controlling APP trafficking and sorting in neurons. Mutation on the Y682 residue to glycine (Y682G) leads to altered APP sorting in hippocampal neurons that favors its accumulation in intracellular compartments and the release of soluble APPα. Such alterations induce premature aging and learning and cognitive deficits in APP Y682G mutant mice (APP (YG/YG) ). Here, we report that Y682G mutation affects formation of the APP complex with sortilin-related receptor (SorLA), resulting in endo-lysosomal dysfunctions and neuronal degeneration. Moreover, disruption of the APP/SorLA complex changes the trafficking pathway of SorLA, with its consequent increase in secretion outside neurons. Mutations in the SorLA gene are a prognostic factor in AD, and changes in SorLA levels in cerebrospinal fluid are predictive of AD in humans. These results might open new possibilities in comprehending the role played by SorLA in its interaction with APP and in the progression of neuronal degeneration. In addition, they further underline the crucial role played by Y682 residue in controlling APP trafficking in neurons.

No MeSH data available.


Related in: MedlinePlus