Experimental models of prion‐like protein propagation

Hasegawa, Masato

doi:10.1111/neup.12656

Cited by 6 publications

(7 citation statements)

References 47 publications

(75 reference statements)

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“…Recently, a growing body of evidence has suggested that misfolded αSyn has prionlike properties, in which the native form of αSyn is converted into misfolded forms, and are transmitted from cell to cell, leading to its spread throughout the brain [130]. In recent years, the injection of αSyn preformed fibrils into the brain parenchyma of rodents has been applied for modeling the propagation of αSyn pathology in PD [131]. Although applying such injection experiments in Drosophila is difficult because of its small brain size, genetically induced fly models of αSyn transmission are expected to be established in the future, like as in other neurodegenerative disease models [132][133][134][135].…”

Section: Discussionmentioning

confidence: 99%

Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson’s Disease

Suzuki

Sango

Nagai

2022

IJMS

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α-Synuclein (αSyn) plays a major role in the pathogenesis of Parkinson’s disease (PD), which is the second most common neurodegenerative disease after Alzheimer’s disease. The accumulation of αSyn is a pathological hallmark of PD, and mutations in the SNCA gene encoding αSyn cause familial forms of PD. Moreover, the ectopic expression of αSyn has been demonstrated to mimic several key aspects of PD in experimental model systems. Among the various model systems, Drosophila melanogaster has several advantages for modeling human neurodegenerative diseases. Drosophila has a well-defined nervous system, and numerous tools have been established for its genetic analyses. The rapid generation cycle and short lifespan of Drosophila renders them suitable for high-throughput analyses. PD model flies expressing αSyn have contributed to our understanding of the roles of various disease-associated factors, including genetic and nongenetic factors, in the pathogenesis of PD. In this review, we summarize the molecular pathomechanisms revealed to date using αSyn-expressing Drosophila models of PD, and discuss the possibilities of using these models to demonstrate the biological significance of disease-associated factors.

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Section: Discussionmentioning

confidence: 99%

Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson’s Disease

Suzuki

Sango

Nagai

2022

IJMS

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“…This conceptualization by coupling molecular and structural templates for AD pathogenesis was so attractive that sparked experimental studies trying to show how tau molecules template themselves to orchestrate NFT formation as presented in this symposium by Hasegawa. 13 It is really exciting if such experimental approach was successful in replicating AD pathogenesis, at least in part so that disease-specific therapeutic approaches can be tested on these animal models based on this Braak-prion hypothesis. However, the concept of "prion" has been interpreted arbitrarily by each researcher, with different points of view and experimental paradigms.…”

Section: Hierarchal Spread Of Neurofibrillary Tangles Interpreted As mentioning

confidence: 99%

“…Therefore, pathologically modified tau provides a “a molecular template” that may propagate unidirectionally along “a structural template,” serially connected from the parahippocampal gyrus to the hippocampus proper, then limbic, association and primary cortices. This conceptualization by coupling molecular and structural templates for AD pathogenesis was so attractive that sparked experimental studies trying to show how tau molecules template themselves to orchestrate NFT formation as presented in this symposium by Hasegawa 13 . It is really exciting if such experimental approach was successful in replicating AD pathogenesis, at least in part so that disease‐specific therapeutic approaches can be tested on these animal models based on this Braak‐prion hypothesis.…”

Section: Hierarchal Spread Of Neurofibrillary Tangles Interpreted As mentioning

confidence: 99%

Neurofibrillary changes undergoing morphological and biochemical changes – How does tau with the profile shift of from four repeat to three repeat spread in Alzheimer brain?

Uchihara

2020

Neuropathology

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The concept of the hierarchal spread of neurofibrillary tangles (NFTs) from the hippocampus to the cortex in Alzheimer's disease (AD)/aging brains, initially proposed by Braak and Braak, revolutionized our understanding by putatively explaining that tau lesions are being unidirectionally extended along neural connections. Because pathological misfolding of tau can serve as a seed to induce identical misfolding on normal tau, this prion-like property is considered to represent a molecular mechanism that may explain such lesion spread. However, double labeling studies for three repeat (3R) and four repeat (4R) tau demonstrated a profile shift in these tau isoforms along chronological change: initially positive only for 4R in early pretangles, gradual involvement of 3R in mature NFTs, and finally replaced by 3R in advanced ghost tangles. This profile shift is hardly explained by aggregation of a single tau molecule. Surprisingly, this profile shift from 4R to 3R tau is shared with the hierarchal spread of NFT around the hippocampus, which is hardly explained by a simple mechanism such as propagation of a single tau molecule. Some molecules other than tau or non-materialist influences such as neuronal activity may be candidate mechanisms to explain this regional profile shift if it is mediated by neural connections. Because this profile shift is shared with brainstem NFTs, it may instead represent a cell autonomous phenomenon, tightly linked with progression of AD but not necessarily linked with prion-like propagation along neural connections. In addition, we recently clarified that posttranslational deamidation of 4R tau at asparagine 279 to aspartate is a marker for AD, distinct from progressive supranuclear palsy (PSP)/corticobasal degeneration (CBD). This may provide another axis to see how AD-NFTs develop and how their 4R tau is distinct from 4R tau of PSP/CBD. Because tau species and their distributions are disease-specific, molecular homogenization, such as "tauopathy" to encompass AD, PSP/CBD and Pick body disease, is just an oversimplification that may obscure fundamental distinctions between human diseases. Careful reference to the realities of human brain disease may provide a solid and fruitful basis to improve diagnostic and therapeutic strategies to tackle these intractable diseases.

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“…Tau protein is capable of replicating its pathogenicity by aggregating itself like prion. This prion‐like property may play a major role in propagating tau lesions (prion hypothesis based on experimental truths) along neural connections, as discussed by Hasegawa 4 . The mechanistic relation between this prion hypothesis (experimental truths) and Braak's scheme (realities in the human brain) has been attracting enthusiastic attention.…”

mentioning

confidence: 99%

“…This prion-like property may play a major role in propagating tau lesions (prion hypothesis based on experimental truths) along neural connections, as discussed by Hasegawa. 4 The mechanistic relation between this prion hypothesis (experimental truths) and Braak's scheme (realities in the human brain) has been attracting enthusiastic attention. The Braak-prion hypothesis could be considered a general principle and provide a comprehensive explanation for protein aggregation and its propagation along neural connections to engender disease-specific distribution and disease-specific sets of clinical manifestations.…”

mentioning

confidence: 99%