Homozygous alpha-synuclein p.A53V in familial Parkinson's disease

Yoshino, Hideaki; Hirano, Minoru; Stoessl, A. Jon; Imamichi, Yoko; Ikeda, Aya; Li, Yuanzhe; Funayama, Manabu; Yamada, Ikuko; Nakamura, Yusaku; Sossi, Vesna; Farrer, Matthew J.; Nishioka, Kenya; Hattori, Nobutaka

doi:10.1016/j.neurobiolaging.2017.05.022

Cited by 106 publications

(72 citation statements)

References 27 publications

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“…The preNAC steric zipper in the rod structure is associated with six PD familial mutation sites (E46K, H50Q, G51D, A53E, A53T, and A53V; Fig. 4a ) 13 – 18 , with the potential to disrupt the preNAC zipper of fibril core in the rod structure (Fig. 3f ).…”

Section: Resultsmentioning

confidence: 99%

Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel

et al. 2018

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α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 Å resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent β-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs.

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Section: Resultsmentioning

confidence: 99%

Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel

et al. 2018

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“…Two types of mutations in the SNCA gene have been linked to autosomal dominant forms of PD, highlighting distinct mechanisms by which ␣-Syn aggregation can be triggered: (i) increased gene dosage and (ii) point mutations enhancing ␣-Syn aggregation propensity. The latter, including A30P [37], E46K [38], H50Q [39,40], G51D [41], and A53T [42], A53V [43], and A53E [44] (see Fig. 1), have been discovered by genetic screens in families with hereditary PD and directly influence ␣-Syn aggregation to different extents and via discrete pathways [45].…”

Section: Snca Mutations Reveal Unique Features Of ␣-Syn Toxicity and mentioning

confidence: 99%

Protein Quality Control Pathways at the Crossroad of Synucleinopathies

Mattos

Wentink

Nussbaum-Krammer

et al. 2020

JPD

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The pathophysiology of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and many others converge at alpha-synuclein (␣-Syn) aggregation. Although it is still not entirely clear what precise biophysical processes act as triggers, cumulative evidence points towards a crucial role for protein quality control (PQC) systems in modulating ␣-Syn aggregation and toxicity. These encompass distinct cellular strategies that tightly balance protein production, stability, and degradation, ultimately regulating ␣-Syn levels. Here, we review the main aspects of ␣-Syn biology, focusing on the cellular PQC components that are at the heart of recognizing and disposing toxic, aggregate-prone ␣-Syn assemblies: molecular chaperones and the ubiquitin-proteasome system and autophagy-lysosome pathway, respectively. A deeper understanding of these basic protein homeostasis mechanisms might contribute to the development of new therapeutic strategies envisioning the prevention and/or enhanced degradation of ␣-Syn aggregates.

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“…The discovery of seven missense mutations, A53T, A30P, E46K, H50Q, G51D, A53V and A53E [6,[71][72][73][74][75][76][77], as well as duplication and triplication [78,79] of the SNCA gene encoding for α-syn as a cause of several PD familial cases undoubtedly rises the interest of the field towards SNCA gene targeting. Moreover, the association between α-syn expression levels and the severity of the pathology [80,81] in sporadic and familial cases, strongly reinforced the link of SNCA gene expression to the pathophysiology of PD.…”

Section: Reducing α-Syn Synthesismentioning

confidence: 99%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Homozygous alpha-synuclein p.A53V in familial Parkinson's disease

Cited by 106 publications

References 27 publications

Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel

Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel

Protein Quality Control Pathways at the Crossroad of Synucleinopathies

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

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