Sortilin acts as an endocytic receptor for α‐synuclein fibril

Ishiyama, Shun; Hasegawa, Takafumi; Sugeno, Naoto; Kobayashi, Junpei; Yoshida, Shun; Miki, Yasuo; Wakabayashi, Keiji; Fukuda, Mitsunori; Kawata, Yasushi; Nakamura, Takaaki; Sato, Kazuki; Ezura, Michinori; Kikuchi, Akio; Takeda, Atsushi; Akiyama, Masashi

doi:10.1096/fj.202201605rr

Cited by 5 publications

(1 citation statement)

References 75 publications

(166 reference statements)

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“…This is supported by previous studies in which the deletion of VPS35 in yeast impaired the transport of VPS10 (a human sortilin homolog) from the endosomes to the TGN, resulting in the accumulation of aggregated proteins because of transport failure from the TGN to the degradation pathway [ 7 ]. It is also interesting in the context of our recent finding that aS fibrils were bound to sortilin on the cell surface and transported via the endolysosomal pathway [ 66 ]. The unexpected result in the present study, that the solubility of aS was altered by R33, is worth further discussion.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of SNX1-retromer axis in pharmacogenetic models of Parkinson’s disease

Yoshida,

Hasegawa,

Nakamura

et al. 2024

Cell Death Discov.

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Since the identification of vacuolar protein sorting (VPS) 35, as a causative molecule for familial Parkinson’s disease (PD), retromer-mediated endosomal machinery has been a rising factor in the pathogenesis of the disease. The retromer complex cooperates with sorting nexin (SNX) dimer and DNAJC13, another causal molecule in PD, to transport cargoes from endosomes to the trans-Golgi network, and is also involved in mitochondrial dynamics and autophagy. Retromer dysfunction may induce neuronal death leading to PD via several biological cascades, including misfolded, insoluble α-synuclein (aS) accumulation and mitochondrial dysfunction; however, the detailed mechanisms remain poorly understood. In this study, we showed that the stagnation of retromer-mediated retrograde transport consistently occurs in different PD-mimetic conditions, i.e., overexpression of PD-linked mutant DNAJC13, excess aS induction, or toxin-induced mitochondrial dysfunction. Mechanistically, DNAJC13 was found to be involved in clathrin-dependent retromer transport as a functional modulator of SNX1 together with heat shock cognate 70 kDa protein (Hsc70), which was controlled by the binding and dissociation of DNAJC13 and SNX1 in an Hsc70 activity-dependent manner. In addition, excess amount of aS decreased the interaction between SNX1 and VPS35, the core component of retromer. Furthermore, R33, a pharmacological retromer chaperone, reduced insoluble aS and mitigated rotenone-induced neuronal apoptosis. These findings suggest that retrograde transport regulated by SNX1-retromer may be profoundly involved in the pathogenesis of PD and is a potential target for disease-modifying therapy for the disease.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of SNX1-retromer axis in pharmacogenetic models of Parkinson’s disease

Yoshida,

Hasegawa,

Nakamura

et al. 2024

Cell Death Discov.

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Changes in the Public IgM Repertoire and its Idiotypic Connectivity in Alzheimer’s Disease and Frontotemporal Dementia

Pashova-Dimova,

Petrov,

Karachanak-Yankova

et al. 2024

Preprint

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Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are prevalent neurodegenerative disorders. Early diagnosis is challenging due to the lack of definitive biomarkers and reliance on invasive procedures. Immune biomarkers, particularly those reflecting the interaction between the central nervous system (CNS) and the peripheral immune system, have shown promise for non-invasive detection through blood samples. This study investigates the reactivity of serum IgM and IgG from AD and FTD patients against a library of mimotopes representing public IgM reactivities in healthy donors. Serum samples from AD, FTD, and other neurodegenerative dementias (ND), and controls were tested on peptide microarrays. The samples were pooled to mitigate individual variability. The reactivity data were analyzed using graphs to represent the cross-reactivity networks. The analysis revealed distinct reactivity patterns for the studied groups. Public IgM reactivities showed significant correlations with neurodegenerative conditions, with AD and FTD exhibiting loss or gain of specific IgM reactivities. Graph analysis highlighted significant differences in graph density, clustering, and assortativity parameters between disease and control groups. Idiotypic reactivities, particularly in IgM, were more connected in healthy controls compared to those with neurodegenerative diseases. Furthermore, clusters of reactivities showed significant distinctions between AD and FTD, with IgG reactivities providing additional differentiation. A number of self proteins related to neurodegeneration proved to have sequences homologous to disease associated mimotopes. Thus, the public IgM repertoire, characterized by its broad reactivity and inherent autoreactivity, offers valuable insights into the immunological alterations in neurodegenerative diseases. The study supports the potential of IgM and IgG reactivity profiles as another compartment of non-invasive biomarkers for early diagnosis and differentiation of AD and FTD.

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Imaging spatial transcriptomics reveals molecular patterns of vulnerability to pathology in a transgenic α-synucleinopathy model

Horan-Portelance,

Iba,

Acri

et al. 2024

Preprint

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One of the unifying pathological hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) is the presence of misfolded, aggregated, and often phosphorylated forms of the protein α-synuclein in neurons. α-Synuclein pathology appears in select populations of neurons throughout various cortical and subcortical regions, and little is currently known about why some neurons develop pathology while others are spared. Here, we utilized subcellular-resolution imaging-based spatial transcriptomics (IST) in a transgenic mouse model that overexpresses wild-type human α-synuclein (α-syn-tg) to evaluate patterns of selective neuronal vulnerability to α-synuclein pathology. By performing post-IST immunofluorescence for α-synuclein phosphorylated at Ser129 (pSyn), we identified cell types in the cortex and hippocampus that were vulnerable or resistant to developing pSyn pathology. Next, we investigated the transcriptional underpinnings of the observed selective vulnerability using a set of custom probes to detect genes involved in α-synuclein processing and toxicity. We identified expression of the kinase:substrate pairPlk2, which phosphorylates α-synuclein at Ser129, and humanSNCA(hSNCA), as underlying the selective vulnerability to pSyn pathology. Finally, we performed differential gene expression analysis, comparing non-transgenic cells to pSyn-and pSyn+α-syn-tg cells to reveal gene expression changes downstream ofhSNCAoverexpression and pSyn pathology, which included pSyn-dependent alterations in mitochondrial and endolysosomal genes. This study provides a comprehensive use case of IST, yielding new biological insights into the formation of α-synuclein pathology and its downstream effects in a PD/DLB mouse model.

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Sortilin acts as an endocytic receptor for α‐synuclein fibril

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 5 publications

References 75 publications

Dysregulation of SNX1-retromer axis in pharmacogenetic models of Parkinson’s disease

Dysregulation of SNX1-retromer axis in pharmacogenetic models of Parkinson’s disease

Changes in the Public IgM Repertoire and its Idiotypic Connectivity in Alzheimer’s Disease and Frontotemporal Dementia

Imaging spatial transcriptomics reveals molecular patterns of vulnerability to pathology in a transgenic α-synucleinopathy model

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