A novel function of Huntingtin in the cilium and retinal ciliopathy in Huntington's disease mice

Autoren

Alice Karam
Lars Tebbe
Chantal Weber
Nadia Messaddeq
Laurette Morlé
Pascal Kessler
Uwe Wolfrum
Yvon Trottier

DOI

10.1016/j.nbd.2015.05.008

ISSN

0969-9961

Zeitschrift

Neurobiology of Disease

Sprache

en

Paginierung

15 - 28

Datum der Veröffentlichung

2015

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.nbd.2015.05.008

Datum der Datenerfassung

2022

Titel

A novel function of Huntingtin in the cilium and retinal ciliopathy in Huntington's disease mice

Ausgabe der Zeitschrift

80

Data source: Crossref

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by the toxic expansion of polyglutamine in the Huntingtin (HTT) protein. The pathomechanism is complex and not fully understood. Increasing evidence indicates that the loss of normal protein function also contributes to the pathogenesis, pointing out the importance of understanding the physiological roles of HTT. We provide evidence for a novel function of HTT in the cilium. HTT localizes in diverse types of cilia--including 9 + 0 non-motile sensory cilia of neurons and 9 + 2 motile multicilia of trachea and ependymal cells--which exert various functions during tissue development and homeostasis. In the photoreceptor cilium, HTT is present in all subciliary compartments from the base of the cilium and adjacent centriole to the tip of the axoneme. In HD mice, photoreceptor cilia are abnormally elongated, have hyperacetylated alpha-tubulin and show mislocalization of the intraflagellar transport proteins IFT57 and IFT88. As a consequence, intraflagellar transport function is perturbed and leads to aberrant accumulation of outer segment proteins in the photoreceptor cell bodies and disruption of outer segment integrity, all of which precede overt cell death. Strikingly, endogenous mouse HTT is strongly reduced in cilia and accumulates in photoreceptor cell bodies, suggesting that HTT loss function contributes to structural and functional defects of photoreceptor cilia in HD mouse. Our results indicate that cilia pathology participates in HD physiopathology and may represent a therapeutic target.

Addresses

Institute of Genetics and Molecular and Cellular Biology, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France.

Autoren

Alice Karam
Lars Tebbe
Chantal Weber
Nadia Messaddeq
Laurette Morlé
Pascal Kessler
Uwe Wolfrum
Yvon Trottier

DOI

10.1016/j.nbd.2015.05.008

eISSN

1095-953X

Externe Identifier

PubMed Identifier: 25989602

Funding acknowledgements

Association Connaître les Syndrômes Cérébelleux (CSC):
European Union/Framework program: 241955
Institut National de la Santé et de la Recherche Médicale (INSERM):
FAUN-Stiftung, Nuremberg:
Centre National de la Recherche Scientifique (CNRS):
University of Strasbourg:
Deutsche Forschungsgemeinschaft GRK 1044:
Retina-France:

Open access

false

ISSN

0969-9961

Zeitschrift

Neurobiology of disease

Schlüsselwörter

Retina
Cilia
Microtubules
Animals
Mice, Transgenic
Humans
Mice
Huntington Disease
Disease Models, Animal
Nerve Tissue Proteins
Nuclear Proteins
Female
Male
Photoreceptor Cells
HEK293 Cells
Huntingtin Protein

Sprache

eng

Medium

Print-Electronic

Online publication date

2015

Paginierung

15 - 28

Datum der Veröffentlichung

2015

Status

Published

Datum der Datenerfassung

2015

Titel

A novel function of Huntingtin in the cilium and retinal ciliopathy in Huntington's disease mice.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

80

Data source: Europe PubMed Central

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by the toxic expansion of polyglutamine in the Huntingtin (HTT) protein. The pathomechanism is complex and not fully understood. Increasing evidence indicates that the loss of normal protein function also contributes to the pathogenesis, pointing out the importance of understanding the physiological roles of HTT. We provide evidence for a novel function of HTT in the cilium. HTT localizes in diverse types of cilia--including 9 + 0 non-motile sensory cilia of neurons and 9 + 2 motile multicilia of trachea and ependymal cells--which exert various functions during tissue development and homeostasis. In the photoreceptor cilium, HTT is present in all subciliary compartments from the base of the cilium and adjacent centriole to the tip of the axoneme. In HD mice, photoreceptor cilia are abnormally elongated, have hyperacetylated alpha-tubulin and show mislocalization of the intraflagellar transport proteins IFT57 and IFT88. As a consequence, intraflagellar transport function is perturbed and leads to aberrant accumulation of outer segment proteins in the photoreceptor cell bodies and disruption of outer segment integrity, all of which precede overt cell death. Strikingly, endogenous mouse HTT is strongly reduced in cilia and accumulates in photoreceptor cell bodies, suggesting that HTT loss function contributes to structural and functional defects of photoreceptor cilia in HD mouse. Our results indicate that cilia pathology participates in HD physiopathology and may represent a therapeutic target.

Date of acceptance

2015

Autoren

Alice Karam
Lars Tebbe
Chantal Weber
Nadia Messaddeq
Laurette Morlé
Pascal Kessler
Uwe Wolfrum
Yvon Trottier

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/25989602

DOI

10.1016/j.nbd.2015.05.008

eISSN

1095-953X

Zeitschrift

Neurobiol Dis

Schlüsselwörter

Cilia
Huntingtin
Huntington's disease
Photoreceptor
Animals
Cilia
Disease Models, Animal
Female
HEK293 Cells
Humans
Huntingtin Protein
Huntington Disease
Male
Mice
Mice, Transgenic
Microtubules
Nerve Tissue Proteins
Nuclear Proteins
Photoreceptor Cells
Retina

Sprache

eng

Country

United States

Paginierung

15 - 28

PII

S0969-9961(15)00170-9

Datum der Veröffentlichung

2015

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2016

Titel

A novel function of Huntingtin in the cilium and retinal ciliopathy in Huntington's disease mice.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

80

Data source: PubMed

A novel function of Huntingtin in the cilium and retinal ciliopathy in Huntington's disease mice

Tools