New Perspectives In NAD+ Therapeutics: Neurodegenerative Disease

Maintaining NAD+ levels seems to, hence, sustain basal metabolic function and health in neurons.

New Perspectives In NAD+ Therapeutics: Neurodegenerative Disease

New Perspectives in NAD+ Therapeutics: Neurodegenerative Disease

Although the elimination of neurons by axonal degradation plays a role in normal nervous system development, aberrant neuronal cell death is typical of insults such as trauma, and chemical toxicity or of aging and neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (for review, see Wang et al., 2012).

Controversial Links between NMNAT and Neurodegenerative Phenotypes
Axon degradation had originally been assumed to be a passive process. However, this view changed with the characterization of the naturally occurring Wallerian degeneration slow (WldS) dominant mutation (Conforti et al., 2000). Rodent carriers of this mutation displayed a dramatic reduction in axonal degeneration in both central and peripheral neurons. The WldS mutant protein is a chimeric protein composed of the complete sequence of NMNAT1 fused to the ubiquitination factor E4B at the N terminus (Conforti et al., 2000, Mack et al., 2001). Efforts from diverse labs have since confirmed that it is the NMNAT enzymatic activity that is required to delay axon degeneration (Araki et al., 2004, Conforti et al., 2009, Gilley and Coleman, 2010, Llopis et al., 2000, Sasaki et al., 2009, Yahata et al., 2009, Yan et al., 2010), probably by promoting an increase in NAD+-directed SIRT1 activity (Araki et al., 2004). Interestingly, WldS mutant mice exhibit enhanced insulin secretion from isolated islets with an improvement in glucose homeostasis, also via an NAD+-directed activation of SIRT1 (Wu et al., 2011). Another study specifically demonstrated that it is the cytosolic distribution of NMNAT proteins that is crucial for slowing Wallerian degeneration (Sasaki et al., 2009). Further work should define changes in nuclear and cytosolic NAD+ levels, as most studies measure NAD+ in whole brain lysate, the outcome of which is confounded by the high level of NAD+ found in neuronal mitochondria.

NAD+ Precursors Protect against Neurodegenerative Disease
Following the injury of neurons, there is an induction of multiple transcripts for NAD+ biosynthetic enzymes, including a more than 20-fold increase in NRK2, which catalyzes the synthesis of NAD+ from NR, suggesting a compensatory response to elevate NAD+ levels (Sasaki et al., 2006). In line with this, the pretreatment of neurons with either high levels of NAD+ in cell culture, or precursors such as NMN or NR, protects against axonal degeneration following axotomy, hearing loss caused by excess manganese toxicity, or even noise-induced hearing loss in mice (Brown et al., 2014, Gerdts et al., 2015, Sasaki et al., 2006, Wang et al., 2014b). Similarly, rodent studies have demonstrated that pharmacological doses of NAM increases NAD+ biosynthesis and provides protection against ischemia (Klaidman et al., 2003, Sadanaga-Akiyoshi et al., 2003), fetal-alcohol-induced neurodegeneration (Ieraci and Herrera, 2006), and fetal ischemic brain injuries (Feng et al., 2006) by preventing NAD+ depletion. Further supporting the role of NAD+ in neuroprotection, a high-throughput screen identified an aminopropyl carbazole chemical P7C3 (Pieper et al., 2010), which was only recently discovered to be a pharmacological activator of NAMPT (Wang et al., 2014a), but had previously been shown to possess neuroprotective activity in models of traumatic brain injury (Yin et al., 2014), Parkinson’s disease (De Jesús-Cortés et al., 2012), and amyotrophic lateral sclerosis (Tesla et al., 2012). Increasing the activity of existing NAMPT using similar pharmacological approaches may therefore improve NAD+ depletion in aged animals, exhibiting reduced NAMPT and impairments in neural stem/progenitor cell self-renewal and differentiation, a treatment phenomenon already demonstrated using NMN on aging mice (Stein and Imai, 2014). In another model of neuronal degeneration, raised NAD+ levels after CR attenuated increases in AD-type β-amyloid content in a rodent model of AD (Qin et al., 2006). NAM was also able to improve β-amyloid peptide (1–42)-induced oxidative damage and therefore protect against neurodegeneration (Turunc Bayrakdar et al., 2014a, Turunc Bayrakdar et al., 2014b). Similarly, exposing neuronal cells to toxic prion proteins, to model protein misfolding in Alzheimer’s and Parkinson’s disease, induced NAD+ depletion that was improved with exogenous NAD+ or NAM (Zhou et al., 2015). Additionally, NR has been shown to improve the AD phenotype via PGC-1α-mediated β-secretase (BACE1) degradation and the induction of mitochondrial biogenesis (Gong et al., 2013).

Maintaining NAD+ levels seems to, hence, sustain basal metabolic function and health in neurons. Furthermore, based on the preliminary evidence above, NR might have a privileged position among different NAD+ precursors in the prevention of neurodegeneration, as the effect of NR may be enhanced by the increase in NRK2 during axonal damage.

The Role of PARPs in Neurodegeneration
The depletion of NAD+ in neurodegeneration has been generally attributed to the activation of PARP enzymes. Well-known neurodegenerative DNA repair disorders include ataxia-telangiectasia (AT), Cockayne syndrome (CS), and xeroderma pigmentosum group A (XPA), all of which demonstrate mitochondrial dysregulation due to SIRT1 inhibition and a reduction in mitophagy, the process of autophagic clearance of defective mitochondria (Fang et al., 2014). The reduction in SIRT1 activity and mitophagy in XPA-, CSB-, and ATM-deficient cells can be attributed to the aberrant activation of PARP1, as reflected by the ability of PARP inhibitor AZD2281 (olaparib) to rescue the mitochondrial defect in cells and to extend the lifespan of xpa-1 mutant worms (Fang et al., 2014). In extension of these findings, using NR or a PARP inhibitor both improved the phenotype of a mouse model of Cockayne Syndrome group B (CSB), an accelerated aging disorder featuring the disinhibition of PARP activity by CSB protein, through SIRT1-mediated improvements of metabolic, mitochondrial, and transcriptional alterations (Scheibye-Knudsen et al., 2014). Similarly, augmented PARylation in the Csa−/−/Xpa−/− (CX) mouse model of cerebellar ataxia was reduced upon NR treatment, which improved NAD+ levels, SIRT1 activity, and mitochondrial function (Fang et al., 2014). Both interventions using NAD+ precursors or PARP inhibition could hence be helpful to improve neurodegenerative phenotypes.

Carles Cantó Keir J. Menzies Johan Auwerx Open Archive June 25, 2015 DOI:https://doi.org/10.1016/j.cmet.2015.05.023