Demonstration of prion-like properties of mutant huntingtin fibrils in both in vitro and in vivo paradigms

Acta Neuropathologica
Maria MasnataFrancesca Cicchetti

Abstract

In recent years, evidence has accumulated to suggest that mutant huntingtin protein (mHTT) can spread into healthy tissue in a prion-like fashion. This theory, however, remains controversial. To fully address this concept and to understand the possible consequences of mHTT spreading to Huntington's disease pathology, we investigated the effects of exogenous human fibrillar mHTT (Q48) and huntingtin (HTT) (Q25) N-terminal fragments in three cellular models and three distinct animal paradigms. For in vitro experiments, human neuronal cells [induced pluripotent stem cell-derived GABA neurons (iGABA) and (SH-SY5Y)] as well as human THP1-derived macrophages, were incubated with recombinant mHTT fibrils. Recombinant mHTT and HTT fibrils were taken up by all cell types, inducing cell morphology changes and death. Variations in HTT aggregation were further observed following incubation with fibrils in both THP1 and SH-SY5Y cells. For in vivo experiments, adult wild-type (WT) mice received a unilateral intracerebral cortical injection and R6/2 and WT pups were administered fibrils via bilateral intraventricular injections. In both protocols, the injection of Q48 fibrils resulted in cognitive deficits and increased anxiety-like behavior....Continue Reading

References

Nov 17, 1983·Nature·J F GusellaA Y Sakaguchi
Feb 12, 2002·Neuroscience and Biobehavioral Reviews·Robert Lalonde
Feb 25, 2003·Nature Neuroscience·Melanie Meyer-LuehmannMathias Jucker
Sep 23, 2006·Science·Melanie Meyer-LuehmannMathias Jucker
Jan 24, 2007·Lancet·Francis O Walker
Nov 6, 2007·Acta Neuropathologica·Jean Paul G Vonsattel
Jun 27, 2008·Movement Disorders : Official Journal of the Movement Disorder Society·Wendy PhillipsRoger A Barker
May 23, 2009·Experimental Neurology·Jenny SassoneAndrea Ciammola
Aug 5, 2009·Proceedings of the National Academy of Sciences of the United States of America·Paula DesplatsSeung-Jae Lee
Mar 24, 2010·Nature Reviews. Molecular Cell Biology·Patrik BrundinRon Kopito
May 25, 2010·Journal of Visualized Experiments : JoVE·Stephan J GuyenetGwenn A Garden
Nov 30, 2010·Neuroscience Letters·Erika AllenJane E Cavanaugh
Jan 20, 2011·The Journal of Clinical Investigation·Christian HansenPatrik Brundin
Sep 13, 2011·International Review of Neurobiology·Anton ReinerPaula Dietrich
Dec 17, 2011·PloS One·Shaheen AkhtarSarah E Lloyd
Mar 1, 2012·Neuron·Alix de CalignonBradley T Hyman
Apr 10, 2012·Progress in Molecular Biology and Translational Science·Zhiqiang Zheng, Marc I Diamond
Jun 28, 2012·Biophysical Journal·Laura PieriRonald Melki
Jul 10, 2012·Current Opinion in Neurology·Ainhi D Ha, Victor S C Fung
Sep 8, 2012·Journal of Huntington's Disease·Michelle NeveklovskaScott O Zeitlin
Oct 12, 2012·Brain Structure & Function·Huazheng LiangGeorge Paxinos
Dec 18, 2012·Neurodegenerative Disease Management·Chris Tang, Andrew Feigin
Mar 4, 2014·Nature Neuroscience·Andrea CrottiChristopher K Glass
May 7, 2014·Annals of Neurology·Francesca CicchettiThomas B Freeman
Jul 8, 2014·Neuropsychology·Janet K WilliamsUNKNOWN PREDICT-HD Investigators and Coordinators of the Huntington Study Group
Dec 17, 2014·The Journal of Biological Chemistry·Elodie MonsellierRonald Melki
May 9, 2015·Brain : a Journal of Neurology·Romina VuonoRoger A Barker
Aug 2, 2015·Cell·UNKNOWN Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium
Oct 17, 2015·The American Journal of Psychiatry·Eric A EppingUNKNOWN PREDICT-HD Investigators and Coordinators of the Huntington Study Group
Nov 13, 2015·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Christopher B DivitoRebecca P Seal
Mar 13, 2016·Brain : a Journal of Neurology·Maud GratuzeEmmanuel Planel
May 26, 2016·Acta Neuropathologica·Iksoo JeonJihwan Song

❮ Previous
Next ❯

Citations

Aug 17, 2019·Journal of Neurochemistry·Erich E WankerSigrid Schnoegl
Jan 31, 2020·Stem Cells Translational Medicine·Bhairavi SrinageshwarJulien Rossignol
Aug 23, 2020·Biomolecules·Carl Alexander SandhofCarmen Nussbaum-Krammer
Mar 13, 2020·Frontiers in Immunology·Oluwaseun FatobaToshihide Yamashita
Apr 30, 2020·International Journal of Molecular Sciences·Fiona LimanaqiFrancesco Fornai
Dec 18, 2020·Frontiers in Neurology·Maria MasnataFrancesca Cicchetti
Feb 25, 2021·Journal of Neurology·Melanie Alpaugh, Francesca Cicchetti
Mar 13, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xiao-Tong WangYu-He Yuan
Apr 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Tessa SinnigeRichard I Morimoto
May 13, 2021·Ageing Research Reviews·Chia-Lung Chuang, Fabio Demontis
Jan 21, 2022·Molecular Therapy : the Journal of the American Society of Gene Therapy·Melanie AlpaughFrancesca Cicchetti

❮ Previous
Next ❯

Methods Mentioned

BETA
BioShop
filter trap
Enzyme
Linked Immunosorbent Assay
electron microscopy
infrared spectroscopy

Software Mentioned

ImageStudioLite
ImageJ
Prism
Zeiss Zen Imaging
nlme
GraphPad
PAS
RStudio

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.