SIRT1 Promotes Neuronal Fortification in Neurodegenerative Diseases through Attenuation of Pathological Hallmarks and Enhancement of Cellular Lifespan

Abstract

Neurodegeneration is a complex neurological phenomenon characterized by disturbed coherence in neuronal efflux. Progressive neuronal loss and brain damage due to various age-related pathological hallmarks perturb the behavioral balance and quality of life. Sirtuins have been widely investigated for their neuroprotective role, with SIRT1 being the most contemplated member of the family. SIRT1 exhibits significant capabilities to enhance neurogenesis and cellular lifespan by regulating various pathways, which makes it an exciting therapeutic target to inhibit neurodegenerative disease progression. SIRT1 mediated neuronal fortification involves modulation of molecular co-factors and biochemical pathways responsible for the induction and sustenance of pro-inflammatory and pro-oxidative environment in the cellular milieu. In this review, we present the major role played by SIRT1 in maintaining cellular strength through the regulation of genomic stability, neuronal growth, energy metabolism, oxidative stress, inhibiting mechanisms and anti-inflammatory responses. The therapeutic significance of SIRT1 has been put into perspective through a comprehensive discussion about its ameliorating potential against neurodegenerative stimuli in a variety of diseases that characteristically impair cognition, memory and motor coordination. This review enhances the acquaintance concerned with the neuroprotective potential of SIRT1 and thus promotes the development of novel SIRT1 regulating therapeutic agents and strategies.

Keywords: SIRT1; genomic stability; neuoroprotection; neurodegenerative disease.; neurogenesis; oxidative stress.

Fig. (1)

Ageing is one of the most prominent factors of neurodegeneration. Age related neurodegeneration progresses due to a fatal cause-effect loop. Aged brain has significantly diminished capability of DNA repair. The resulting genomic instability deteriorates intercellular communication, thereby affecting the normal functioning of the neuronal circuits. It also enhances inflammation in the neurons which is further facilitated by reduced autophagy and mitophagy. While reduced autophagy results in the accumulation of toxic misfolded proteins and inflammation promoters, the hindrance in mitochondrial functioning caused due to reduced mitophagy renders reactive oxygen species unchecked that elevates oxidative stress. These free radicals further damage the DNA and hamper mitochondrial biogenesis and fuel the cause-effect loop of neurodegeneration. Such progressive and continuous neuronal loss overcomes the natural process of neurogenesis and thereby leads to irreversible brain damage and subsequent onset of neurodegenerative diseases. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

The calorie restriction (CR) process is known to activate the SIRT1 molecule that leads to the regulation of various genes and proteins. SIRT1 regulates the p53 unit and provides substantial protection against cell apoptosis, which is one of the leading causes of cell-death. The histone deacetylation potential of the SIRT1 molecule results in increased life span through gene silencing. SIRT1 is also responsible for the regulation of PGC1-α, which is responsible for up-keeping mitochondrial integration and functioning. Energy failure and imbalance in mitochondrial functioning potentiate cellular apoptosis. Neuroinflammation is another important aspect in neuropathology. SIRT1 is responsible for the downregulation of NF-kB activity that has been found to lower neuroinflammation and oxidative stress. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (3)

SIRT1 regulates a variety of molecular targets that have certain direct effect on neuronal health and cell survival. SIRT1 regulates FoxO3a to inhibit the expression of ROCK1 gene. Aβ localization gets inhibited due to reduced expression of ROCK1 gene and that significantly reduces neurodegeneration. SIRT1 also decreases apoptosis in cells by inhibiting the expression of cathepsin B and iNOS through regulation of NF-κB gene. This process of gene silencing eventually leads to reduced inflammation and neurodegeneration through decreased apoptosis and Aβ localization. SIRT1 is also responsible for maintaining cellular health by ensuring proper functioning. It enhances PGC1-α expression while reducing synuclein aggregation. This reduces oxidative stress in the brain and helps in the proper functioning of mitochondria. Deacetylation of p53 and suppression of FoxO protein mediated through increased SIRT1 expression also reduces cellular loss in the brain. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (4)

The figure depicts the central role of SIRT1 as a regulatory molecule in various neurological disorders, namely Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Wallerian degeneration, as discussed in the review. SIRT 1 regulates the expression of associated proteins and enzymes via inhibition or promotion mechanism. SIRT1 is also known to affect neurophysiological mechanisms by regulating the enzyme action. The positive and negative signs indicate SIRT1 mediated promoter and inhibitor activities, respectively. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (5)

Epilepsy is characterized by increased oxidative stress in the brain. Increased concentration of ROS hampers the energy balance in the brain and thereby leads to mitochondrial dysfunctioning. SIRT1 mediated regulation of PARP1 through NAD⁺ ensures smooth mitochondrial functioning. SIRT1 promotes detoxification of ROS through detoxifying enzymes that are activated due to the activation of PGC-1α. ROS detoxification is also enhanced due to SIRT1 mediated activation of Forkhead box class O. Reduced ROS concentration promotes intact mitochondrial integrity. Activation of PGC-1α also augments mitochondrial biogenesis, which is vital for cellular survival. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (6)

SIRT1 is a promoter of axonal health. Remyelination inhibits axonal damage and thereby enhances neuronal survival. SIRT1 mediated inhibition of Mash1 and activation of BDNF increases neuronal lifespan and thereby significantly improves coherence in the neuronal circuit. This plays an important role in various vital brain functions. Increased cellular survival and enhanced intercellular communication owing to diminished neuronal apoptosis signifies ameliorating functions of SIRT1 against neurodegeneration driven fatal molecular and biochemical alterations.

Fig. (7)

ALS is characterized by motor neuron dysfunctioning leading to hampered voluntary movement. The SOD1 protein mutations result into the accumulation of toxic protein aggregates, thereby inducing significant neurotoxicity. ALS pathology also involves downregulation of AMPK pathway that promotes neuroinflammation and subsequent motor neuron dysfunctioning. Upregulation of AMPK pathway through SIRT1 activation not only lowers the inflammatory response but also enhances mitochondrial biogenesis. Reduced toxic protein aggregates and increased energy balance in the neuronal circuit dilute the adverse effects of neurotoxic stimuli and therefore imparts significant protection against motor neuron damage.

Fig. (8)

Ischemic stroke is characterized by restricted cerebral blood flow (CBF) that leads to deficiency of oxygen and energy in the cerebral tissues. Neuronal damage following restricted CBF is augmented by enhanced neuroinflammation and oxidative stress load. SIRT1 regulates various pathways that are responsible for attenuating responses aggravating the ischemic insult. SIRT1 upregulation checks p53 and PARP1 activity and diminishes NF-kB signaling, thereby negatively regulating the pro-inflammatory environment. The deacetylation of eNOS by SIRT1 inhibits the restriction of CBF and thus prevents neuronal damage in cerebral tissues due to oxygen and energy deficiency. SIRT1 maintains the energy balance in the cellular environment also through the regulation of free radical concentration. SIRT1 mediated enhancement of BDNF and PGC-1α expression and inhibition of UCP2 activity augments mitochondrial biogenesis and thereby reduces oxidative stress load. Such protective effects of SIRT1 make it an effective therapeutic target in ischemic stroke management.