Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases

Guo, Jing; Lee, Virginia M.‐Y.

doi:10.1038/nm.3457

Cited by 563 publications

(549 citation statements)

References 136 publications

(150 reference statements)

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“…Recent experimental studies and observations in humans (e.g. grafted neurons in PD) have shown similarities in spreading, including cell-to-cell transmission, and self-perpetuation of other NDD-related proteins [7][8][9][10][11][12][13][14][15][16][17]. The observation of a prion-like internalization process of disease-associated ␣-synuclein in the human brain supported this notion [18].…”

Section: Introductionmentioning

confidence: 88%

Patterns of Tau and α-Synuclein Pathology in the Visual System

Rahimi

Milenković

Kovács

2015

Journal of Parkinson’s Disease

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Abstract.Background: Spreading of misfolded proteins has been suggested for neurodegenerative diseases. The hierarchical distribution of protein deposits in Alzheimer's (AD) and Parkinson's disease (PD) supports this concept. Objectives: To evaluate ␣-synuclein and tau-deposition in the optic pathway as an excellent anatomical model, which follows a strict trajectory including a cortico-geniculate feedback connection. Methods: We immunostained the optic nerve, lateral geniculate nucleus (LGN), and occipital cortex for AT8 (phosphorylated tau), ␣-synuclein, and disease-associated prion protein (PrP) in 47 cases with tau pathology (AD type, argyrophilic grain disease, or progressive supranuclear palsy), 16 PD, and 5 Creutzfeldt-Jakob disease (CJD) cases, respectively. Results: We detected immunoreactivity for all proteins along the optic pathway. The optic nerve showed immunopositivity only in cases with tau (6/8, 75%) or ␣-synuclein (5/7, 71%) pathology. The LGN was involved also frequently (tau: 22/47, 46.8%; ␣-synuclein: 15/16, 93.7%; PrP 5/5, 100%). The occipital cortex was variably affected by tau or ␣-synuclein pathology, but always showed PrP immunoreactivity in the CJD cases. Tau pathology in the LGN correlated with tau immunoreactivity in the occipital cortex and Braak stages of neurofibrillary degeneration. In tauopathies, which do not involve the occipital cortex, like argyrophilic grain disease or progressive supranuclear palsy, tau pathology was more frequently astrocytic in the LGN. Conclusions: Our results have implications 1) for the understanding of disease spreading along neural pathways and 2) for the diagnostic evaluation of the visual system in neurodegenerative proteinopathies as a potential biomarker to evaluate disease progression or subgrouping of cases.

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Section: Introductionmentioning

confidence: 88%

Patterns of Tau and α-Synuclein Pathology in the Visual System

Rahimi

Milenković

Kovács

2015

Journal of Parkinson’s Disease

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“…The observation that the pathology appeared to progress into regions that were synaptically connected led to the idea that pathology was spreading through neuronal circuits (7,8). Converging lines of evidence demonstrated that aggregates of diseaseassociated misfolded proteins, including α-synuclein, tau, and superoxide dismutase 1, are in fact transmissible from cell to cell and that this transmission propagates throughout the brain (9,10). More recently, mutant huntingtin (Htt) aggregates were also shown to spread between neurons in vivo (11).…”

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confidence: 99%

Transcellular spreading of huntingtin aggregates in theDrosophilabrain

Babcock

Ganetzky

2015

Proc. Natl. Acad. Sci. U.S.A.

114

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A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamineexpanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington's disease. Upon expression of this construct in a defined subset of neurons, we demonstrate that protein aggregates accumulate at synaptic terminals and progressively spread throughout the brain. These aggregates are internalized and accumulate within other neurons. We show that Htt aggregates cause non-cell-autonomous pathology, including loss of vulnerable neurons that can be prevented by inhibiting endocytosis in these neurons. Finally we show that the release of aggregates requires N-ethylmalemide-sensitive fusion protein 1, demonstrating that active release and uptake of Htt aggregates are important elements of spreading and disease progression.

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“…121 In recent years, multiple studies have investigated the prion-like capabilities of pathological proteins and protein aggregates associated with various neurodegenerative diseases. 124 Exosomal secretion of small fractions of amyloid-β peptides has been observed. 125 Internalization of aggregates containing α-synuclein, tau, ALS-associated proteins and polyglutamine proteins has also been shown in cultured cells.…”

Section: Primary Cilia: Secretory Organelles?mentioning

confidence: 99%

Primary cilia and autophagic dysfunction in Huntington’s disease

2015

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Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by a single-gene mutation: a CAG expansion in the huntingtin (HTT) gene that results in production of a mutated protein, mutant HTT, with a polyglutamine tail (polyQ-HTT). Although the molecular pathways of polyQ-HTT toxicity are not fully understood, because protein misfolding and aggregation are central features of HD, it has long been suspected that cellular housekeeping processes such as autophagy might be important to disease pathology. Indeed, multiple lines of research have identified abnormal autophagy in HD, characterized generally by increased autophagic induction and inefficient clearance of substrates. To date, the origin of autophagic dysfunction in HD remains unclear and the search for actors involved continues. To that end, recent studies have suggested a bidirectional relationship between autophagy and primary cilia, signaling organelles of most mammalian cells. Interestingly, primary cilia structure is defective in HD, suggesting a potential link between autophagic dysfunction, primary cilia and HD pathogenesis. In addition, because polyQ-HTT also accumulates in primary cilia, the possibility exists that primary cilia might play additional roles in HD: perhaps by disrupting signaling pathways or acting as a reservoir for secretion and propagation of toxic, misfolded polyQ-HTT fragments. Here, we review recent research suggesting potential links between autophagy, primary cilia and HD and speculate on possible pathogenic mechanisms and future directions for the field.

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Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases

Cited by 563 publications

References 136 publications

Patterns of Tau and α-Synuclein Pathology in the Visual System

Patterns of Tau and α-Synuclein Pathology in the Visual System

Transcellular spreading of huntingtin aggregates in theDrosophilabrain

Primary cilia and autophagic dysfunction in Huntington’s disease

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