Tissue transglutaminase crosslinks ataxin-1: possible role in SCA1 pathogenesis

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Spinocerebellar ataxia-1 (SCA1) is a neurodegenerative disorder caused by mutations in the ataxin-1 gene.
• Transglutaminase type 2 (TG2) is an enzyme known to crosslink proteins and has been linked to other neurodegenerative diseases like Huntington's disease.

Purpose of the Study:

• To investigate whether transglutaminase type 2 (TG2) crosslinks the spinocerebellar ataxia-1 (SCA1) gene product, ataxin-1.
• To explore the role of TG2 in the formation of ataxin-1 aggregates.

Main Methods:

• HeLa cells expressing GFP-tagged ataxin-1 with varying glutamine lengths were incubated with TG2.
• TG2 activity was assessed using the inhibitor cystamine.
• SCA1 transgenic mice were analyzed for TG2 localization and ataxin-1 aggregation.
• In vitro crosslinking assays were performed using purified TG2 and nuclear extracts.

Main Results:

• Exogenous TG2 induced covalent crosslinking of ataxin-1 in cell lysates, which was inhibited by cystamine.
• SCA1 transgenic mice showed elevated nuclear TG2, even before the formation of ataxin-1 nuclear aggregates.
• In vitro experiments demonstrated that TG2 can promote the formation of insoluble ataxin-1 aggregates.

Conclusions:

• Ataxin-1 is a substrate for TG2-mediated crosslinking.
• TG2 may translocate to the nucleus in response to mutant ataxin-1 accumulation in early SCA1 stages.
• TG2-mediated crosslinking of ataxin-1 is a potential mechanism contributing to SCA1 pathogenesis.