SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network

Hung, Christy; Tuck, Eleanor J.; Stubbs, Victoria; Lee, Sven J. van der; Aalfs, Cora M.; Spaendonk, Resie van; Scheltens, Philip; Hardy, John; Holstege, Henne; Livesey, Frederick J.

doi:10.1016/j.celrep.2021.109259

Cited by 56 publications

(76 citation statements)

References 44 publications

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“…Endosome enlargement has been described to be the first cytopathological marker of AD, before the emergence of plaques and tangles [ 8 ]. Several human AD cell models, namely hiNs originating from sporadic and familial AD patients [ 27 ], hiNs carrying fAD APP and PSEN1 mutations [ 34 ] and hiNs knocked-out for the AD risk gene SORL1 [ 25 , 32 ], recapitulate these endosomal defects similarly to what we observed in the BIN1iso1 overexpressing hiNs. In AD and Down syndrome, these defects are associated with an overactivation of Rab5 [ 47 ] and overactivation of Rab5 in mice mimics AD-like endosomal dysfunction [ 48 ].…”

Section: Discussionsupporting

confidence: 58%

“…However, in our study, loss of Appl , the Drosophila ortholog of APP, did not rescue BIN1iso1-induced neurodegeneration, suggesting that APP β-CTF does not mediate BIN1iso1 toxicity. The involvement of APP β-CTF have also been questioned in SORL1 knocked-out hiNs with contradictory results in two studies showing APP β-CTF-dependent or -independent endosomal defects [ 25 , 32 ]. Another putative intermediate is Ras and Rab Interactor 3 (RIN3), a guanine nucleotide exchange factor (GEF) for the Rab5 small GTPase family, which is located in a GWAS-defined AD susceptibility locus [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

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The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

Lambert

Saha

Landeira

et al. 2022

acta neuropathol commun

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The Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer’s disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (BIN1iso9), induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

Lambert

Saha

Landeira

et al. 2022

acta neuropathol commun

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“…Interestingly, SORL1 is also linked to the more common, late-onset form of AD [ 45 , 70 ] and its expression is lost in sporadic AD brains [ 4 , 21 , 59 , 89 ]. When modeled in human neurons, SORL1 depletion phenocopies APP and PSEN mutations by causing endosomal swelling [ 37 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons

Mishra

Knupp

Szabo

et al. 2022

Cell. Mol. Life Sci.

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Background Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer’s disease (AD). Recent studies have established that loss of SORL1, as well as mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD’s cytopathological hallmark. Acting together with the retromer trafficking complex, SORL1 has been shown to regulate the recycling of the amyloid precursor protein (APP) out of the endosome, contributing to endosomal swelling and to APP misprocessing. We hypothesized that SORL1 plays a broader role in neuronal endosomal recycling and used human induced pluripotent stem cell-derived neurons (hiPSC-Ns) to test this hypothesis. We examined endosomal recycling of three transmembrane proteins linked to AD pathophysiology: APP, the BDNF receptor Tropomyosin-related kinase B (TRKB), and the glutamate receptor subunit AMPA1 (GLUA1). Methods We used isogenic hiPSCs engineered to have SORL1 depleted or to have enhanced SORL1 expression. We differentiated neurons from these cell lines and mapped the trafficking of APP, TRKB and GLUA1 within the endosomal network using confocal microscopy. We also performed cell surface recycling and lysosomal degradation assays to assess the functionality of the endosomal network in both SORL1-depleted and -overexpressing neurons. The functional impact of GLUA1 recycling was determined by measuring synaptic activity. Finally, we analyzed alterations in gene expression in SORL1-depleted neurons using RNA sequencing. Results We find that as with APP, endosomal trafficking of GLUA1 and TRKB is impaired by loss of SORL1. We show that trafficking of all three cargoes to late endosomes and lysosomes is affected by manipulating SORL1 expression. We also show that depletion of SORL1 significantly impacts the endosomal recycling pathway for APP and GLUA1 at the level of the recycling endosome and trafficking to the cell surface. This has a functional effect on neuronal activity as shown by multi-electrode array (MEA). Conversely, increased SORL1 expression enhances endosomal recycling for APP and GLUA1. Our unbiased transcriptomic data further support SORL1’s role in endosomal recycling. We observe altered expression networks that regulate cell surface trafficking and neurotrophic signaling in SORL1-depleted neurons. Conclusion Collectively, and together with other recent observations, these findings suggest that one role for SORL1 is to contribute to endosomal degradation and recycling pathways in neurons, a conclusion that has both pathogenic and therapeutic implications for Alzheimer’s disease.

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“…In polarized MDCK cells, SorLA is targeted to the basolateral membrane and to sorting endosomes, in cultured neurons, to the somato-dendritic area [ 25 ]. In SorLA deficient hiPSC-derived neurons, altered endosomal trafficking of APP was confirmed, but an overall endosome enlargement was also observed [ 26 , 27 ]. SorLA ablation seemed to disrupt endosomal cargo processing and cause intracellular traffic jams, supporting a broader role in regulating endosomal transport and sorting [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…In SorLA deficient hiPSC-derived neurons, altered endosomal trafficking of APP was confirmed, but an overall endosome enlargement was also observed [ 26 , 27 ]. SorLA ablation seemed to disrupt endosomal cargo processing and cause intracellular traffic jams, supporting a broader role in regulating endosomal transport and sorting [ 26 , 27 ]. Therefore, understanding the determinants of SorLA’s subcellular itinerary might be pertinent for understanding neuronal endosomal sorting in general.…”

Section: Introductionmentioning

confidence: 99%

The adaptor protein PICK1 targets the sorting receptor SorLA

et al. 2022

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SorLA is a member of the Vps10p-domain (Vps10p-D) receptor family of type-I transmembrane proteins conveying neuronal endosomal sorting. The extracellular/luminal moiety of SorLA has a unique mosaic domain composition and interacts with a large number of different and partially unrelated ligands, including the amyloid precursor protein as well as amyloid-β. Several studies support a strong association of SorLA with sporadic and familial forms of Alzheimer’s disease (AD). Although SorLA seems to be an important factor in AD, the large number of different ligands suggests a role as a neuronal multifunctional receptor with additional intracellular sorting capacities. Therefore, understanding the determinants of SorLA’s subcellular targeting might be pertinent for understanding neuronal endosomal sorting mechanisms in general. A number of cytosolic adaptor proteins have already been demonstrated to determine intracellular trafficking of SorLA. Most of these adaptors and several ligands of the extracellular/luminal moiety are shared with the Vps10p-D receptor Sortilin. Although SorLA and Sortilin show both a predominant intracellular and endosomal localization, they are targeted to different endosomal compartments. Thus, independent adaptor proteins may convey their differential endosomal targeting. Here, we hypothesized that Sortilin and SorLA interact with the cytosolic adaptors PSD95 and PICK1 which have been shown to bind the Vps10p-D receptor SorCS3. We observed only an interaction for SorLA and PICK1 in mammalian-two-hybrid, pull-down and cellular recruitment experiments. We demonstrate by mutational analysis that the C-terminal minimal PDZ domain binding motif VIA of SorLA mediates the interaction. Moreover, we show co-localization of SorLA and PICK1 at vesicular structures in primary neurons. Although the physiological role of the interaction between PICK1 and SorLA remains unsolved, our study suggests that PICK1 partakes in regulating SorLA’s intracellular itinerary.

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SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network

Cited by 56 publications

References 44 publications

The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons

The adaptor protein PICK1 targets the sorting receptor SorLA

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