FOR INFORMATIONAL PURPOSES ONLY
………..Wallerian Degeneration…………….
Axons are considered to be a particularly vulnerable component of the nervous system; impairment of a neuron's axon leads to an effective silencing of a neuron's ability to communicate with other cells. 1
The nervous system has therefore evolved plasticity mechanisms for adapting to axonal damage. These include acute mechanisms that promote the degeneration and clearance of damaged axons and, in some cases, the initiation of new axonal growth and synapse formation to rebuild lost connections. 1
One such mechanism, Wallerian Degeneration, is an active programmed process of degeneration of an axon that is triggered by nerve damage or insult. 2
Axonal degeneration is observed in a variety of contexts in both the central and peripheral nervous systems. The pathological signaling programs that regulate the progression of axonal degeneration have been studied using Wallerian degeneration models. 3
Axons are essential for nervous system function and axonal pathology is a common hallmark of many neurodegenerative diseases. Over a century and a half since the original description of Wallerian axon degeneration, advances over the past five years have heralded the emergence of a comprehensive, mechanistic model of an endogenous axon degenerative process that can be activated by both injury and disease. 4
Wallerian degeneration is a conserved axonal self-destruction program implicated in a number of neurological diseases. It is driven in part, by the activation of the NAD+ degrading SARM1 pathway, eventually leading to axonal fragmentation and degeneration. 5
Axon degeneration is an early pathological event in many neurological diseases. 6
Sterile Alpha and Toll Interleukin Receptor Motif-containing protein 1 (SARM1) has been identified as a key driver of axon degeneration and an emerging therapeutic target for diseases that exhibit Wallerian-like degeneration. These diseases include traumatic brain injury, peripheral neuropathy, and neurodegenerative diseases. 7
Thus genes, like SARM1, that drive the Wallerian degeneration process, are excellent candidates as therapeutic targets for treatment of conditions that involve axon degeneration including Parkinson’s Disease. 8
Another pathway associated with active axon degeneration involves Dual Leucine-zipper Kinase (DLK) [also known as mitogen-activated protein kinase kinase kinase 12 (MAP3K12)] which is expressed predominately in neuronal cells. DLK and its downstream enzyme, c-Jun N-terminal kinase (JNK), play major roles in neuron apoptosis and degeneration. 9
The following paragraphs review how these diverse processes are influenced by the therapeutically targetable enzyme SARM1 and how SARM1 catalyzes the breakdown of NAD+, which, when unmitigated, can lead to depletion of this essential metabolite and ultimately axonal degeneration. 1
……… Pro-survival versus axon degeneration…..
Nicotinamide adenine dinucleotide (NAD+) is one of the most abundant metabolites in the human body and is predominantly synthesized through the NAD+ salvage pathway in mammalian cells, where nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme. 10
NAD+ is a critical cofactor in numerous reactions, with its role in energy metabolism (glycolysis, TCA cycle, oxidative phosphorylation, and fatty acid oxidation) being the most well-known. NAD+ also functions as a substrate for certain NAD+-consuming enzymes, including sirtuins, poly-(ADP-ribose) polymerases (Parps), CD38/157, and sterile α and TIR motif-containing protein 1 (SARM1). 10
Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme that mediates various redox reactions. Particularly, mitochondrial NAD plays a critical role in energy production pathways. 11
The balance between axon survival and self-destruction is intimately tied to axonal NAD+ metabolism. These mechanistic insights may enable axon-protective therapies for a variety of human neurodegenerative diseases including peripheral neuropathy, traumatic brain injury and potentially ALS and Parkinson's. 4
Axonal integrity is maintained by the opposing actions of the survival factors NMNAT2 and STMN2 and pro-degenerative molecules DLK and SARM1. 4
During axon degeneration, NAD+ levels are largely controlled by the enzyme: SARM1 (sterile alpha and toll interleukin motif containing protein 1). 12
SARM1 activity decreases the concentration of NAD+ 12
SARM1 promotes neurodegeneration by catalyzing the hydrolysis of NAD+ to form a mixture of ADPR and cADPR. 7
SARM1 knockout mice (mice bred to genetically lack the SARM1 gene) show decreased neurodegeneration in animal models of axon degeneration, highlighting the therapeutic potential of targeting this novel NAD+ hydrolase. 12
Since genetic SARM1 knockdown prevents degeneration, it suggests that SARM1 inhibitors will also likely be efficacious in treating diseases characterized by neurodegeneration. 7
Consistent with this hypothesis is the observation that NAD+ supplementation is axoprotective. 7
Understanding metabolism of nicotinamide adenine dinucleotide (NAD+) and the functional regulation of Sarm1 has generated great progress in this field. Described here is our current understanding of the axonal degeneration mechanism, with special reference to the biology related to Sarm1. 3
…………. NAD+ Metabolism……………..
The first step in the synthesis of NAD+ from nicotinic acid amide (or nicotinamide, NAM) NAM is catalyzed by the Nicotinamide phophoribosyltransferase (NAMPT) enzyme. By virtue of this enzymatic reaction, NAM is transformed into nicotinamide mononucleotide (NMN), which is then used by NMNATs to synthesize NAD+ 13
However, Nicotinamide Mono-Nucleotide (NMN) accumulation can activate SARM1, elevating cellular cADPr levels while depleting NAD+, ultimately leading to non-apoptotic cell death. SARM1 is known to be an important contributor in regulating axonal degeneration (discussed below). 13
SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. 14
Recently, researchers elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN). 14
In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to the SARM1 allosteric binding site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 binding site, which in turn activates the SARM1 NAD+ hydrolase; ultimately depleting NAD+ 14
Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. 14
This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. 14
Counterintuitively, attempting to salvage neurons by raising neuronal NAD+ levels through raising the NAD+ precursor, NMN, may inadvertently activate the pro-neurodegenerative (sARM1) pathway in vulnerable axons.
Less is known about the second pro-neurodegenerative enzyme Dual Leucine-zipper Kinase (DLK).
After axonal insult and injury, Dual Leucine-zipper Kinase (DLK) conveys retrograde pro-degenerative signals to neuronal cell bodies via its downstream target c-Jun N-terminal kinase (JNK). Researchers recently reported that such signals critically require modification of DLK by the fatty acid palmitate, via a process called palmitoylation. Compounds that inhibit DLK palmitoylation could thus reduce neurodegeneration, but identifying such inhibitors requires a suitable assay.15
Experimental results seem to suggest an application of this knowledge in patient care.
Pharmacological strategies that modulate NMN and NAD+ metabolism, namely the inhibition of the NMN-synthesizing enzyme NAMPT, activation of the nicotinic acid riboside (NaR) salvage pathway and inhibition of the NMNAT2-degrading DLK MAPK pathway in an axotomy model in vitro were explored. 5
Results show that NAMPT inhibition causes a significant delay of Wallerian axon degeneration. This neuroprotection is related to reduction of NMN by blocking the enzyme responsible for its synthesis (NAMPT) and elevation of NAD+ using the alternative precursor molecule Nicotinamide Riboside (NR). 5
Other studies show how NR could increase NAD+ levels in cultured mammalian cells, rodent tissues and peripheral blood mononuclear cells in humans after oral administration. The ability of NR to act as a NAD+ precursor in mammalian cells and organisms has since been replicated by multiple independent labs. 13
Supplementation of NAMPT inhibition with Nicotinamide Riboside has an enhanced effect that does not depend on timing of intervention and leads to robust neural protection. 5
In humans, NR has been administered to doses up to 2 g/day, without any apparent side effects. 13
The observed neuroprotection could be further extended by the addition of DLK inhibition.
Therefore, DLK inhibitors may potentially be effective in the inhibition of the DLK/JNK pathway to provide greatly needed treatments for many neurological diseases and disorders resulting from neurodegeneration. 9
Metabolite analyses revealed complex effects indicating that NAMPT and DLK/MAPK inhibition act by reducing NMN levels, ameliorating NAD+ loss and suppressing SARM1 activity. 5
……………… NAD, SARM1 and Parkinson’s ……………………..
NAD regulates energy metabolism, DNA damage repair, gene expression, and stress response. Numerous studies have demonstrated the involvement of NAD metabolism in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and retinal degenerative diseases. 11
Mitochondrial dysfunction is considered crucial pathogenesis for neurodegenerative diseases such as AD and PD. Maintaining appropriate NAD levels is important for mitochondrial function. Indeed, decreased NAD levels are observed in AD and PD, and supplementation of NAD precursors ameliorates disease phenotypes by activating mitochondrial functions. 11
Summary: Targets to impede neurodegeneration.
1. Maintain adequate levels of neuronal NAD+.
2. Use Nicotinic Riboside
3. Avoid NMN
4. Block NAMPT
a. Mangostin inhibits NAMPT 16–18
5. Block SARM1
a. berberine inhibits SARM1. 7
6. Block DLK
a. palmitoylation inhibitors
.......... References.........
1. Waller, T. J. & Collins, C. A. Multifaceted roles of SARM1 in axon degeneration and signaling. Front. Cell. Neurosci. 16, 958900 (2022).
2. Wallerian Degeneration. Physiopedia physio-pedia.com/Wallerian_....
3. Funakoshi, M. & Araki, T. Mechanism of initiation and regulation of axonal degeneration with special reference to NMNATs and Sarm1. Neurosci. Res. S0168-0102(21)00223–6 (2021) doi:10.1016/j.neures.2021.11.002.
4. Figley, M. D. & DiAntonio, A. The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease. Curr. Opin. Neurobiol. 63, 59–66 (2020).
5. Alexandris, A. S. et al. Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons. Neurobiol. Dis. 171, 105808 (2022).
6. Bratkowski, M. et al. Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease. Neuron 110, 3711-3726.e16 (2022).
7. Loring, H. S., Parelkar, S. S., Mondal, S. & Thompson, P. R. Identification of the first noncompetitive SARM1 inhibitors. Bioorg. Med. Chem. 28, 115644 (2020).
8. Peters, O. M. et al. Genetic diversity of axon degenerative mechanisms in models of Parkinson’s disease. Neurobiol. Dis. 155, 105368 (2021).
9. Abdel-Magid, A. F. Dual Leucine Zipper Kinase Inhibitors: Potential Treatments for Neurodegenerative Diseases. ACS Med. Chem. Lett. 6, 11–12 (2014).
10. Lundt, S. & Ding, S. NAD+ Metabolism and Diseases with Motor Dysfunction. Genes 12, 1776 (2021).
11. Hikosaka, K., Yaku, K., Okabe, K. & Nakagawa, T. Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases. Nutr. Neurosci. 24, 371–383 (2021).
12. Icso, J. D. & Thompson, P. R. The chemical biology of NAD+ regulation in axon degeneration. Curr. Opin. Chem. Biol. 69, 102176 (2022).
13. Cercillieux, A., Ciarlo, E. & Canto, C. Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations. Cell. Mol. Life Sci. 79, 463 (2022).
14. Sasaki, Y. et al. Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection. Exp. Neurol. 345, 113842 (2021).
15. Martin, D. D. O. et al. Identification of Novel Inhibitors of DLK Palmitoylation and Signaling by High Content Screening. Sci. Rep. 9, 3632 (2019).
16. Ding, Y.-Y. et al. α-Mangostin reduced the viability of A594 cells in vitro by provoking ROS production through downregulation of NAMPT/NAD. Cell Stress Chaperones 25, 163–172 (2020).
17. Hu, Y.-H. et al. α-Mangostin Alleviated Inflammation in Rats With Adjuvant-Induced Arthritis by Disrupting Adipocytes-Mediated Metabolism-Immune Feedback. Front. Pharmacol. 12, 692806 (2021).
18. Tao, M. et al. α-Mangostin Alleviated Lipopolysaccharide Induced Acute Lung Injury in Rats by Suppressing NAMPT/NAD Controlled Inflammatory Reactions. Evid.-Based Complement. Altern. Med. ECAM 2018, 5470187 (2018).
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