Neurochemical Research (2019) 44:2423–2434 https://doi.org/10.1007/s11064-019-02809-1 ORIGINAL PAPER PGC‑1α, Sirtuins and PARPs in Huntington’s Disease and Other Neurodegenerative Conditions: NAD+ to Rule Them All Alejandro Lloret1,2 · M. Flint Beal1 Received: 28 January 2019 / Revised: 2 May 2019 / Accepted: 2 May 2019 / Published online: 7 May 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract In this review, we summarize the available published information on the neuroprotective efects of increasing nicotinamide adenine dinucleotide (NAD+) levels in Huntington’s disease models. We discuss the rationale of potential therapeutic beneft of administering nicotinamide riboside (NR), a safe and efective NAD+ precursor. We discuss the agonistic efect on the Sirtuin1-PGC-1α-PPAR pathway as well as Sirtuin 3, which converge in improving mitochondrial function, decreasing ROS production and ameliorating bioenergetics defcits. Also, we discuss the potential synergistic efect of increasing NAD+ combined with PARPs inhibitors, as a clinical therapeutic option not only in HD, but other neurodegenerative conditions. Keywords Huntington’s disease · NAD+ · Nicotinamide Riboside · Sirtruins · PGC-1 alpha · PARPs Introduction [1]. HD is characterized by striatal degeneration, behavio- ral and cognitive impairments, and involuntary choreiform Mitochondrial dysfunction and ROS production are a com- movements. The toxic efects of mHtt include transcriptional mon pathogenic features present among many neurodegen- dysregulation, oxidative damage, excitotoxicity and bioener- erative conditions, such as Alzheimer’s, Parkinson’s and getic defects [2–4]. One element in which all these pathways Huntington’s disease (HD). HD is an autosomal-dominant seem to converge is PGC-1α, whose activation is modulated, neurodegenerative disorder that is considered as the fag- among others, by the NAD+ dependent deacetylase Sirtuin ship for studying the pathogenic pathways involved in neural 1 (SIRT1). NAD+ cellular levels also regulate two other death as well as for devising therapeutic intervention strate- targets of interest in neurodegeneration: Sirtuin 3 (SIRT3), gies. This is because its monogenetic cause, the relative pre- and Poly (ADP-ribose) polymerase 1 (PARP1). SIRT3 is a cision to predict the age of onset, its neural specifcity and mitochondrial deacetylase that regulates mitochondrial tran- availability of diferent pre-clinical models that re-capitulate scription in response to ROS stress. PARP1 is a member of a the human phenotypes. More importantly, the number of family of enzymes that polymerize ADP ribose units using patients sufering from this condition for which there is no NAD+ as a substrate and transfers them to acceptor proteins current efective treatment or cure. The mutation consists in response to DNA damage, and events such as chromatin of an expansion of an unstable CAG repeat located in exon remodeling, nuclear transcription, and cellular death [5]. 1 of the gene IT15. This results in a poly-glutamine expan- Based on the role that NAD+ plays in all these pathways that sion (> 36) in the protein product, mutant huntingtin (mHtt) are altered in HD, we discuss the rationale for its potential therapeutic value. Special issue: In honor of Prof. VeraAdam-Vizi. PGC‑1α and HD * Alejandro Lloret [email protected] PGC-1α is a transcriptional co-factor involved in energy 1 Feil Family Brain and Mind Research Institute, Weill production and mitochondrial biogenesis, cellular respi- Cornell Medical College, 1400 York Street, 5th Floor, Room ration and ROS detoxifcation. Its activity is regulated in A-501, New York, NY 10065, USA diferent tissues through many stimuli such as: exercise, 2 Present Address: NeuCyte Pharmaceuticals, 1561 Industrial in the muscle; cold, in brown fat [6]; and fasting, in the Road, San Carlos, CA 94070, USA Vol.:(0123456789)1 3 2424 Neurochemical Research (2019) 44:2423–2434 liver [7]. It induces glucose uptake and fatty acid oxidation and glutathione peroxidase (GPx1) [37]. CREB regulates (muscle), adaptive thermogenesis (brown fat) and gluco- PGC-1α activity in response to H 2O2, and stimuli such as neogenesis and beta-oxidation of fatty acids (liver) [8–10]. exercise [8, 37, 38]. At a cellular level, there are diferent signaling path- Overexpression of PGC-1α in the N171-82Q HD trans- ways that control PGC-1α expression and activity. PGC-1α genic mice ameliorated motor defcits and it attenuated neu- increases its own expression by an auto-regulatory loop rodegeneration, partly by alleviating oxidative stress [39]. It [11]. Post-translational modifcations such as phosphoryla- also virtually eliminated huntingtin aggregates by activat- tion by AMPK and p38 MAPK; methylation by PRMT1 ing the transcription factor TFEB, a master regulator of the and de-acetylation by SIRT1 promote its activity [12]. autophagy-lysosome pathway. PGC-1α and PGC-1β overex- Phosphorylation by AKT and CLK2; SUMOylation by pression in rat cortical neurons co-transfected with a human SUMO1 and acetylation by GCN5 represses it [13–16]. huntingtin exon containing a 120 CAG expansion restores It is also modulated by cAMP, Ca2+ and CREB [17–20]. cell survival and increases mitochondrial density [40]. Indi- Key fndings reported in the literature point towards rect activation of PGC-1α by means of mitogen- and stress- PGC-1α as a key player in the pathogenesis of HD. activated kinase (MSK-1) [36], and by adipose-derived stem Sequence variation in the PGC-1α gene modifes age of cells (ASCs) exosomes [41] restores mitochondrial func- onset of HD [21–24]. Reported phenotype of PGC-1α tion. Next, we present the neuroprotective efect observed knockout mice show a spongiform pattern of neurode- by increasing active PGC-1α in HD through its modulation generation in the striatum, as well as a marked behavio- by sirtuins 1 and 3. ral hyperactivity phenotype reminiscent of HD [25, 26]. Also, defects in myelination are present in PGC-1α KO mice as well as in R6/2 and BACHD HD transgenic mouse Sirtuin 1 and Sirtuin 3 in HD models [27]. Striata from HD patients, knock-in HD mice, and striatal STHdhQ111 cells (a homozygous cell-based Sirtuins are a family of class III histone deacetylases whose HD model, [28]), show marked reductions in PGC-1α activity depends on NAD +. In humans, there are 7 known mRNA levels, and huntingtin interferes with the CREB/ sirtuins (SIRT1-7) classifed mainly by their cellular locali- TAF4 complex [29]. Expression of PGC-1α is reduced zation (reviewed [42, 43]). SIRT1 and SIRT3 are of special in medium spiny neurons and its down-regulation wors- interest in HD. ens behavioral and neuropathological abnormalities in a SIRT1 mRNA and protein levels are decreased in brain PGC-1α knock-out-/HD knock-in mice (PGC-1α KO/KI) tissue from HD patients [44, 45]. An important role of SIRT1 [29]. Microarray expression data from human brains from in mediating neuroprotection was reported when SIRT1 HD patients showed signifcant reductions in 24 out of 26 overexpression showed a protective efect against motor PGC-1α target genes [30]. PGC-1α mRNA is reduced in dysfunction, and cortical and striatal atrophy, and loss of N171-82Q HD mice. Signifcant hypothermia was found striatal neurons in both N171-82Q and BACHD transgenic in both N171-82Q and R6/2 HD mice, due to impaired mouse models of HD [46, 47]. Brain-specifc knockdown of PGC-1α induction of uncoupling protein 1 (UCP-1) [30]. SIRT1 exacerbated brain pathology while overexpression Stimulation of extra-synaptic NMDA receptors impairs protected in the R6/2 transgenic mouse model of HD [46]. the PGC-1α cascade in HD mice [31]. There is impaired The protective efect required the presence of TORC1. The PGC-1α and PGC-1β function in HD transgenic mice, and expression of BDNF, which is lowered in HD [48], was iden- in HD human muscle biopsies, and human myoblasts [32, tifed as a key target of SIRT1 and TORC1 transcriptional 33]. PGC-1β is a homologue of PGC-1α, which is abun- activity. Mutant Htt interfered with TORC1/CREB to repress dantly expressed in heart, skeletal muscle, brown adipose BDNF transcription, and SIRT1 rescued the defect both tissue and brain and is involved in mitochondrial biogen- in vitro and in vivo. Interestingly, another report shows that esis [34]. BDNF stimulates PGC-1α dependent mitochondrial biogen- There is a markedly impaired ability to upregulate esis and dendritic spine formation and synapses in the hip- PGC-1α in response to an energetic stress in HD transgenic pocampus [49]. In cell culture studies beta-catenin enhanced mice [32, 33]. Reductions in numbers of mitochondria in mutant huntingtin toxicity, whereas SIRT1 overexpression striatal spiny neurons that are HD pathologic grade-depend- protects and reduces FOXO and beta-catenin signaling, and ent correlate with reductions in PGC-1α and TFAM [35]. increases mitochondrial uncoupling protein expression [50]. Mitogen- and stress-activated protein kinase 1 (MSK-1), Treatment of R6/2 HD mouse model with Beta-Lapachone which upregulates PGC-1α, is deficient in the striatum (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran- of HD patients and mice [36]. PGC-1α reduces oxidative 5,6-dione), a small molecule obtained from the bark of the stress, by increasing expression of copper/zinc superox- Lapacho tree, increases the levels of expression of SIRT1 ide dismutase (SOD1), manganese SOD (SOD2), catalase and PGC-1α and ameliorates motor and mitochondrial 1 3 Neurochemical Research (2019) 44:2423–2434 2425 dysfunction [51]. Resveratrol, a phenolic compound found in an 82Q N-terminal Htt fragment), and the R6/2 HD mouse red grapes and red wine, activates SIRT1 and has been tested model [63]. Clinical trials in healthy controls [64] and HD in HD models. Resveratrol treatment of a C. elegans model patients showed that Selisistat is relatively well tolerated. of HD was neuroprotective through activation of SIRT1 and However, there was no evidence of its efcacy since there PGC-1α [52, 53].