Poly ADP-ribose signaling is dysregulated in Huntington disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington disease (HD) is a genetic neurodegenerative disorder caused by CAG repeat expansion in the Huntingtin (HTT) gene.
• While CAG repeat length correlates with onset age, significant variability exists, suggesting other genetic or molecular factors are involved.
• Elevated DNA damage and dysfunction in DNA repair pathways, including the PARP pathway, are implicated in HD pathogenesis.

Purpose of the Study:

• To investigate the role of poly (ADP-ribose) (PAR) metabolism in Huntington disease.
• To explore the interaction between the Huntingtin protein (HTT) and the PARP pathway.
• To identify potential early molecular mechanisms and therapeutic targets for HD.

Main Methods:

• Measurement of cerebrospinal fluid PAR levels in HD mutation carriers and controls.
• Analysis of PAR response in patient-derived induced pluripotent stem cell-derived neurons and fibroblasts.
• Biochemical assays to detect HTT-PAR binding and assess HTT's effect on PARP1 activity.
• Single-molecule visualization of HTT-PAR interactions using atomic force microscopy.

Main Results:

• HD mutation carriers exhibit reduced cerebrospinal fluid PAR levels, even in the premanifest stage.
• HD cells show a diminished PAR response despite elevated DNA damage.
• Huntingtin protein (HTT) binds to PARylated proteins and localizes to mitotic chromosomes.
• Wild-type HTT enhances in vitro PARP1 activity, whereas mutant HTT does not.

Conclusions:

• Altered PAR levels and impaired PAR response are early molecular events in Huntington disease.
• The Huntingtin protein interacts with the PARP pathway, with functional differences between wild-type and mutant forms.
• These findings suggest that targeting the PARP pathway could offer a strategy for early preventive therapies in HD.