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Gene & Protein in Disease Amino acid metabolism in neurodegeneration

that sense amino acid levels and their downstream factors in the surrounding microenvironment. It
effectors in the signaling cascade, can lead to disruptions induces a transcriptional control program that enhances
in cellular homeostasis and have been associated with protein biosynthesis at the cellular level. In the CNS,
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a variety of pathological conditions, including cancer, neurotransmitters, neuromodulators, and hormones
neurological disorders, and other age-related diseases. have been observed to activate this signaling cascade.
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Signaling pathways that sense nutrient availability and Moreover, mTOR is expressed at high levels in the brain,
regulate metabolic responses represent potential points of in particular, in neurons and glial cells. mTOR signaling
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intervention for treating metabolic disorders and diseases also plays a crucial role in the development and maturation
of the CNS. of dendritic growth. Upregulation of mTOR has been
associated with pathological conditions that promote
3.2. Amino acid-sensing signaling networks neurodegeneration and the development of brain tumors.
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In most organisms, homeostasis is achieved through the In this context, the exact role of mTOR signaling in various
equilibrium of anabolism and catabolism through evolved representative neurological disorders will be examined.
nutrient-sensing mechanisms, enabling proper growth and
survival. Amino acid availability is a crucial mediator of 3.2.2. GCN2-integrated stress response pathway
cell metabolism and directly influences cellular responses. The ISR is an intracellular adaptive cytoprotective pathway
Two major amino acid-sensing signaling networks are responsible for the maintenance of cellular integrity and
responsible for sensing the availability of micronutrients in homeostasis. This pathway is activated in response to both
the microenvironment and responding accordingly: (i) the extrinsic and intrinsic stress stimuli. Depending on the
mechanistic target of the rapamycin complex (mTORC) nature of the stressor, different kinases may be activated.
pathway and (ii) the general control non-derepressible To date, research has identified a total of four serine/
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protein of the integrated stress response (GCN2-ISR) threonine kinases within the mammalian system that
pathway. 44 have the ability to activate a common protein target, the
The mTORC pathway is activated in response to eukaryotic translation initiation factor 2α. This activation
amino acid abundance, whereas the GCN2-ISR pathway occurs through the phosphorylation of the alpha subunit
is induced under conditions of amino acid starvation or at serine 51 residue, which serves as a convergence point
deprivation. Both mTOR and GCN2 are serine/threonine for all stress signals. The phosphorylation event triggers
kinases whose activities are tightly and dynamically the activation of activating transcription factor 4 (ATF4),
modulated dependent on the availability of amino acids in leading to a reduction in global protein synthesis. However,
the surrounding cellular microenvironment, as illustrated concurrently, several specific proteins are synthesized
in Figure 1. Furthermore, AMP-activated protein under the transcriptional control of ATF4, facilitating
kinase serves as a negative regulator of mTOR signaling, stress adaptation.
playing a crucial role in mediating energy metabolism The GCN2-ISR is a branch of the ISR pathway that is
by suppressing protein synthesis. In this context, we aim induced by the GCN2 kinase in response to amino acid
to further delineate the mechanisms of these signaling deficiency. Activation of the GCN2 kinase, triggered by
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cascades and the regulatory roles they play in both healthy amino acid deficiency in the cellular microenvironment,
and pathological conditions. leads to the suppression of global translation while
simultaneously inducing a specific transcriptional control
3.2.1. mTOR signaling pathway program for stress adaptation in the eukaryotic systems.
The mTOR is an atypical serine/threonine kinase that belongs Overall, the regulation networks of amino acid response
to the phosphoinositide 3-kinase-related kinase family. It are fundamental for preventing detrimental cellular
consists of two functionally distinct multiprotein complexes: behavior, such as proteotoxicity, which can lead to
mechanistic target of rapamycin complex (mTORC)1 and pathophysiological adaptations.
mTORC2. A key component of mTORC1 is the raptor, This pathway also plays a significant biological role
which is responsible for downstream signaling, whereas the in the brain. In particular, dysregulation of the ISR has
rictor is responsible for the activation of mTORC2. mTOR been implicated in neurodegenerative processes. For
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is a crucial regulator of cellular homeostasis and is involved instance, the accumulation of misfolded or unfolded
in numerous processes, such as proliferation, autophagy, proteins and chronic stress – both common hallmarks
and immune cell differentiation, among others. of neurodegeneration – are known to induce the ISR.
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This nutrient-sensing signaling cascade is activated Notably, a 2020 study demonstrated that inhibiting the
on amino acid abundance and the availability of growth ISR signaling cascade in aged mice unexpectedly resulted

Volume 3 Issue 3 (2024) 6 doi: 10.36922/gpd.3294