Viral alpha-synuclein knockdown prevents spreading synucleinopathy

Sindhu Menon; Rikke H. Kofoed; Fadl Nabbouh; Kristiana Xhima; Yasmeen Al-Fahoum; Tammy Langman; Howard T.J. Mount; Lamya S. Shihabuddin; S. Pablo Sardi; Paul E. Fraser; Joel C. Watts; Isabelle Aubert; Anurag Tandon

doi:10.1093/braincomms/fcab247

Viral alpha-synuclein knockdown prevents spreading synucleinopathy

Sindhu Menon, Rikke H. Kofoed, Fadl Nabbouh, Kristiana Xhima, Yasmeen Al-Fahoum, Tammy Langman, Howard T.J. Mount, Lamya S. Shihabuddin, S. Pablo Sardi, Paul E. Fraser, Joel C. Watts, Isabelle Aubert, Anurag Tandon^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

2 Citationer (Scopus)

Abstract

The accumulation of aggregated alpha-synuclein (a-syn) in Parkinson's disease, dementia with Lewy bodies and multiple system atrophy is thought to involve a common prion-like mechanism, whereby misfolded a-syn provides a conformational template for further accumulation of pathological a-syn. We tested whether silencing a-syn gene expression could reduce native non-aggregated asyn substrate and thereby disrupt the propagation of pathological a-syn initiated by seeding with synucleinopathy-affected mouse brain homogenates. Unilateral intracerebral injections of adeno-associated virus serotype-1 encoding microRNA targeting the asyn gene reduced the extent and severity of both the a-syn pathology and motor deficits. Importantly, a moderate 50% reduction in a-syn was sufficient to prevent the spread of a-syn pathology to distal brain regions. Our study combines behavioural, immunohistochemical and biochemical data that strongly support a-syn knockdown gene therapy for synucleinopathies.

Originalsprog	Engelsk
Artikelnummer	247
Tidsskrift	Brain Communications
Vol/bind	3
Nummer	4
ISSN	2632-1297
DOI	https://doi.org/10.1093/braincomms/fcab247
Status	Udgivet - 2021
Udgivet eksternt	Ja

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title = "Viral alpha-synuclein knockdown prevents spreading synucleinopathy",

abstract = "The accumulation of aggregated alpha-synuclein (a-syn) in Parkinson's disease, dementia with Lewy bodies and multiple system atrophy is thought to involve a common prion-like mechanism, whereby misfolded a-syn provides a conformational template for further accumulation of pathological a-syn. We tested whether silencing a-syn gene expression could reduce native non-aggregated asyn substrate and thereby disrupt the propagation of pathological a-syn initiated by seeding with synucleinopathy-affected mouse brain homogenates. Unilateral intracerebral injections of adeno-associated virus serotype-1 encoding microRNA targeting the asyn gene reduced the extent and severity of both the a-syn pathology and motor deficits. Importantly, a moderate 50% reduction in a-syn was sufficient to prevent the spread of a-syn pathology to distal brain regions. Our study combines behavioural, immunohistochemical and biochemical data that strongly support a-syn knockdown gene therapy for synucleinopathies.",

keywords = "gene silencing, gene therapy, multiple system atrophy, Parkinson's disease, pathology",

author = "Sindhu Menon and Kofoed, {Rikke H.} and Fadl Nabbouh and Kristiana Xhima and Yasmeen Al-Fahoum and Tammy Langman and Mount, {Howard T.J.} and Shihabuddin, {Lamya S.} and Sardi, {S. Pablo} and Fraser, {Paul E.} and Watts, {Joel C.} and Isabelle Aubert and Anurag Tandon",

note = "Publisher Copyright: {\textcopyright} The Author(s) (2021).",

year = "2021",

doi = "10.1093/braincomms/fcab247",

language = "English",

volume = "3",

journal = "Brain Communications",

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T1 - Viral alpha-synuclein knockdown prevents spreading synucleinopathy

AU - Menon, Sindhu

AU - Kofoed, Rikke H.

AU - Nabbouh, Fadl

AU - Xhima, Kristiana

AU - Al-Fahoum, Yasmeen

AU - Langman, Tammy

AU - Mount, Howard T.J.

AU - Shihabuddin, Lamya S.

AU - Sardi, S. Pablo

AU - Fraser, Paul E.

AU - Watts, Joel C.

AU - Aubert, Isabelle

AU - Tandon, Anurag

N1 - Publisher Copyright: © The Author(s) (2021).

PY - 2021

Y1 - 2021

N2 - The accumulation of aggregated alpha-synuclein (a-syn) in Parkinson's disease, dementia with Lewy bodies and multiple system atrophy is thought to involve a common prion-like mechanism, whereby misfolded a-syn provides a conformational template for further accumulation of pathological a-syn. We tested whether silencing a-syn gene expression could reduce native non-aggregated asyn substrate and thereby disrupt the propagation of pathological a-syn initiated by seeding with synucleinopathy-affected mouse brain homogenates. Unilateral intracerebral injections of adeno-associated virus serotype-1 encoding microRNA targeting the asyn gene reduced the extent and severity of both the a-syn pathology and motor deficits. Importantly, a moderate 50% reduction in a-syn was sufficient to prevent the spread of a-syn pathology to distal brain regions. Our study combines behavioural, immunohistochemical and biochemical data that strongly support a-syn knockdown gene therapy for synucleinopathies.

AB - The accumulation of aggregated alpha-synuclein (a-syn) in Parkinson's disease, dementia with Lewy bodies and multiple system atrophy is thought to involve a common prion-like mechanism, whereby misfolded a-syn provides a conformational template for further accumulation of pathological a-syn. We tested whether silencing a-syn gene expression could reduce native non-aggregated asyn substrate and thereby disrupt the propagation of pathological a-syn initiated by seeding with synucleinopathy-affected mouse brain homogenates. Unilateral intracerebral injections of adeno-associated virus serotype-1 encoding microRNA targeting the asyn gene reduced the extent and severity of both the a-syn pathology and motor deficits. Importantly, a moderate 50% reduction in a-syn was sufficient to prevent the spread of a-syn pathology to distal brain regions. Our study combines behavioural, immunohistochemical and biochemical data that strongly support a-syn knockdown gene therapy for synucleinopathies.

KW - gene silencing

KW - gene therapy

KW - multiple system atrophy

KW - Parkinson's disease

KW - pathology

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U2 - 10.1093/braincomms/fcab247

DO - 10.1093/braincomms/fcab247

M3 - Journal article

AN - SCOPUS:85130725113

SN - 2632-1297

VL - 3

JO - Brain Communications

JF - Brain Communications

IS - 4

M1 - 247

ER -

Viral alpha-synuclein knockdown prevents spreading synucleinopathy

Abstract

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