TY - JOUR
T1 - Pathophysiological interplay between O-GlcNAc transferase and the Machado-Joseph disease protein ataxin-3
AU - Sena, Priscila Pereira
AU - Weber, Jonasz J.
AU - Watchon, Maxinne
AU - Robinson, Katherine J.
AU - Wassouf, Zinah
AU - Hauser, Stefan
AU - Helm, Jacob
AU - Abeditashi, Mahkameh
AU - Schmidt, Jana
AU - Hubener-Schmid, Jeannette
AU - Schols, Ludger
AU - Laird, Angela S.
AU - Riess, Olaf
AU - Schmidt, Thorsten
PY - 2021/11/23
Y1 - 2021/11/23
N2 - Aberrant O-GlcNAcylation, a protein posttranslational modification defined by the O-linked attachment of the monosaccharide N-acetylglucosamine (O-GlcNAc), has been implicated in neurodegenerative diseases. However, although many neuronal proteins are substrates for O-GlcNAcylation, this process has not been extensively investigated in polyglutamine disorders. We aimed to evaluate the enzyme O-GlcNAc transferase (OGT), which attaches O-GlcNAc to target proteins, in Machado-Joseph disease (MJD). MJD is a neurodegenerative condition characterized by ataxia and caused by the expansion of a polyglutamine stretch within the deubiquitinase ataxin-3, which then present increased propensity to aggregate. By analyzing MJD cell and animal models, we provide evidence that OGT is dysregulated in MJD, therefore compromising the O-GlcNAc cycle. Moreover, we demonstrate that wild-type ataxin-3 modulates OGT protein levels in a proteasomedependent manner, and we present OGT as a substrate for ataxin-3. Targeting OGT levels and activity reduced ataxin-3 aggregates, improved protein clearance and cell viability, and alleviated motor impairment reminiscent of ataxia of MJD patients in zebrafish model of the disease. Taken together, our results point to a direct interaction between OGT and ataxin-3 in health and disease and propose the O-GlcNAc cycle as a promising target for the development of therapeutics in the yet incurableMJD.
AB - Aberrant O-GlcNAcylation, a protein posttranslational modification defined by the O-linked attachment of the monosaccharide N-acetylglucosamine (O-GlcNAc), has been implicated in neurodegenerative diseases. However, although many neuronal proteins are substrates for O-GlcNAcylation, this process has not been extensively investigated in polyglutamine disorders. We aimed to evaluate the enzyme O-GlcNAc transferase (OGT), which attaches O-GlcNAc to target proteins, in Machado-Joseph disease (MJD). MJD is a neurodegenerative condition characterized by ataxia and caused by the expansion of a polyglutamine stretch within the deubiquitinase ataxin-3, which then present increased propensity to aggregate. By analyzing MJD cell and animal models, we provide evidence that OGT is dysregulated in MJD, therefore compromising the O-GlcNAc cycle. Moreover, we demonstrate that wild-type ataxin-3 modulates OGT protein levels in a proteasomedependent manner, and we present OGT as a substrate for ataxin-3. Targeting OGT levels and activity reduced ataxin-3 aggregates, improved protein clearance and cell viability, and alleviated motor impairment reminiscent of ataxia of MJD patients in zebrafish model of the disease. Taken together, our results point to a direct interaction between OGT and ataxin-3 in health and disease and propose the O-GlcNAc cycle as a promising target for the development of therapeutics in the yet incurableMJD.
KW - Ataxin-3
KW - Machado-
KW - OGlcNAc
KW - OGT
KW - Oseph disease
KW - Spinocerebellar ataxia type 3
UR - http://www.scopus.com/inward/record.url?scp=85120335766&partnerID=8YFLogxK
U2 - 10.1073/pnas.2025810118
DO - 10.1073/pnas.2025810118
M3 - Article
C2 - 34785590
AN - SCOPUS:85120335766
SN - 0027-8424
VL - 118
SP - 1
EP - 12
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 47
M1 - e2025810118
ER -