N6-Furfuryladenine is Protective in Huntington’s Disease Models By Signaling Huntingtin Phosphorylation During DNA Damage Repair

Identification: Truant, Ray


Description

N6-Furfuryladenine is Protective in Huntington's Disease Models By Signaling Huntingtin Phosphorylation During DNA Damage Repair
 
Ray Truant1*, Laura E. Bowie1, Tamara Maiuri1, Melanie Alpaugh2, Michelle Gabriel3, Nicholas Arbez4, Claudia L.K. Hung1,  Shreya Patel1, Jianrun Xia1, Nicholas T. Hertz5, Chris A. Ross4, David Litchfield3, and  Simonetta Sipione2
1Department of Biochemistry and Biomedical Sciences, McMaster University. Hamilton, Canada; 2Department of Pharmacology, University of Alberta, Edmonton, Canada; 3Department of Biochemistry, Western University. London, Canada; 4Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, MD, USA; 5Mitokinin LLC, NY, USA
 
Huntington disease (HD) is an age-onset disease caused by CAG DNA expansion in the huntingtin open reading frame. Normal huntingtin is a scaffold in oxidative DNA damage Base Excision Repair, triggered by ROS-sensing at the ER and a critical phosphorylation in the huntingtin N17 domain.  This triggers interaction with HMGB1 and nuclear entry to RNA speckles. The huntingtin N17 domain is a modulator of mutant huntingtin toxicity, modified at a critical residue by Casein Kinase 2 (CK2). Phosphomimetics of this modification prevent HD phenotypes in animal models, thus defining phosphorylation augmentation of mutant huntingtin as a valid sub-target for HD therapeutic development.
  
We conducted unbiased, machine scored, high content analysis to find compounds that could modulate N17 phosphorylation. One lead from this screen was N6-furfuryladenine (N6FFA), a natural compound. N6FFA is the product of ROS damage on DNA via the Fenton reaction. N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes, eliminates cortical mutant huntingtin inclusions and nets normalized levels of mutant huntingtin.
 
We show that N6FFA restores N17 phosphorylation levels by being salvaged to novel triphosphate form and used as a phosphate donor by CK2 and PINK1 kinases, only.  N17-phosphorylated huntingtin functionally re-distributes and colocalizes with CK2, and N6FFA DNA adducts at sites of induced DNA damage centered on Ataxia Telangiectasia Mutated (ATM) complex.
 
We present a model in which this natural product compound is salvaged to provide a triphosphate "neosubstrate" to signal huntingtin via CK2. This signaling triggers a feedback loop by sending huntingtin back to BER which releases more N6FFA from damaged DNA until the signal is dampened due to repair. This is in the absence of NAD+ and ATP under conditions of DNA damage. We hypothesize effects in HD model systems are by alleviating a mitochondrial "energy crisis" induced by DNA damage via age-onset ROS and subsequent hyper-PARylation of repair factors. We suggest CK2 at DNA,  and PINK1, at mitochondria, have evolved loose triphosphate binding pockets to be able to use atypical triphosphates derived from nucleotide salvage to overcome a signaling block under low ATP conditions in stressed neurons. This data highlights common pathways on mechanism of disease with HD, PD, ALS and genetic ataxias, with multiple polyglutamine ataxia proteins now defined at DNA damage.
 
 

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