Endogenous Mechanisms Of Neuroprotection: To Boost Or Not To Be Part 3
Jul 18, 2024
Mitochondria are transported around the cell by the cytoskeleton, motor proteins, and appropriate adaptors. In neurons, they are mainly trafficked on MTs by the adaptors Miro and Milton/trafficking kinesin-binding protein 1 (TRAK) proteins [161].
The cytoskeleton is one of the main components of the cell's background and is the main determinant of the cell's given shape and mechanical properties. Recent studies have shown that the cytoskeleton can also affect brain function learning and memory.
Neurons in the brain have many long, filamentous projections called dendrites that receive and process signals from other neurons. Telomere continua (TEL) is a cytoskeletal protein that is also common in neurons. Studies have shown that TEL proteins can affect the size and shape of dendrites, thereby affecting neuronal connections and signal processing.
Another cytoskeletal protein, tubulin, can also affect neuronal function. Neurons use tubulin to maintain their shape and connections, and studies have also shown that tubulin can affect the speed of neuronal signal transmission.
In addition to neurons, cytoskeletal proteins in other cells may also affect memory and learning. For example, synaptic connections between neurons are often affected by matrix proteins, a class of proteins in the extracellular matrix. Matrix proteins can affect the persistence and plasticity of synaptic connections, thereby affecting the formation and maintenance of memory.
In summary, the cytoskeleton has a crucial impact on brain function learning, and memory. Understanding the functions and mechanisms of the cytoskeleton can help us better understand the occurrence and development of brain diseases and learning and memory disorders, and provide a deeper scientific basis for the development of related diagnostic and therapeutic methods. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.
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These mitochondria movements within neurons are essential to maintain optimal fitness within the synapses, producing energy, buffering Ca2+, etc. [162]. Mitochondria often localize close to ER, forming mitochondria-associated ER membranes, or mitochondria-associated membranes (MAMs).
These membrane microdomains are reversible tethers that co-regulate and influence a variety of cellular processes, i.e., synthesis/transport of lipids, Ca2+ dynamics/signaling, autophagy, mitochondrial shape and size, apoptosis, and energy metabolism [163].
MAMs are altered in neurological disorders such as AD, PD, and ALS [164]. Mitochondria acts as a hub of ATGs, supplying membranes for the formation of autophagosomes, and modulating autophagic flux [165].
Mitochondria also suffer UPR(mt), and depending on the activated pathway, it has been linked with extended lifespan in worms and mice [166], but its overactivation causes neurodegeneration [167].
Mitochondrial dysfunction arises from an inadequate number of mitochondria, an inability to provide necessary substrates to them, or a dysfunction in their electron transport and ATP-synthesis machinery.
The high levels of ROS and the related reactive species (RNS) can be neutralized by dismutase enzymes and antioxidants [168]. Alterations in these enzymes and certain mitochondrial respiratory complexes have been observed in neurodegenerative diseases such as ALS and PD [169].
Perturbations in mitochondrial number and function severely impair cellular homeostasis and trigger the onset of disease. Therefore, cells pursue to maintain a dynamic balance between the opposing processes of mitochondrial biogenesis and clearance.
The accumulation of dysfunctional mitochondria and/or the loss of its biogenesis produces cell death. Recent therapeutic avenues to prevent neurodegeneration aim to boost mitochondrial biogenesis by modulating NAD+ [170], epigenetic marks [171], or modulating the serotonin axis in the brain [172]. Dysfunctional mitochondrial clearance by mitophagy also yields neuroprotection.
The overexpression of PTEN-induced kinase 1 (PINK1), which is essential for initiating the mitophagy process, increases neuronal survival in a fly model of HD [45]. In addition, NAD+ supplementation reduces neurotoxicity in a PINK1-mutant model of PD [173].
Mitochondria function is crosslinked with ROS and cellular antioxidant response. In that way, the transcription factor Nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) regulates the expression of cytoprotective and detoxifying genes to combat oxidative stress and neuroinflammation, aiming to reduce neural damage.
Therefore, it can be an effective manipulation to delay disease progression in neurodegenerative diseases [174–176]. Under the stimulation of ROS, Nrf2 dissociates from Kelch-like ECH-associated protein (Keap1), thereby regulating the expression of antioxidant enzymes [177].
It has been described that Keap1 mediates the ubiquitination of p62 [178]. When Keap1 is downregulated, p62 accumulates in cells and causes cytotoxicity, while its overexpression promotes the degradation of p62 via the autophagy pathway.
On the other side, p62 activates Nrf2 through the autophagy pathway to form the p62-Keap1-Nrf2-antioxidant responsive element (ARE) pathway and counteracts the oxidative damage caused by ROS [179].
Moreover, Nrf2 forms regulatory loops involved in the regulation of mitochondrial biogenesis. Nrf2 increases the expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) and nuclear respiratory factor (NRF1), which are directly involved in the regulation of mtDNA transcription.
Lastly, Nrf2 regulates the expression of PINK1, which plays a key role in mitophagy induction [180], suggesting that the antioxidant capacity of the cell also impacts on mitochondria state.
Neurodegenerative diseases are related to both the inhibition of the Nrf2 pathway and dysfunction of autophagy, which leads to the accumulation of ROS, senescent organelles, and misfolded proteins [181,182].
Neurodegenerative diseases are related to lots of protein aggregates and ROS, inducing the p62-Keap1-Nrf2 positive feedback axis, which is a protective mechanism in neurons [183,184]. Nrf2 expression is low in AD animal models and AD patient brains [185]. Nrf2 binding to the ARE occurs soon during disease progression, which corresponds with an increase in ROS production [186].
Nrf2 neuroprotects by decreasing ROS generation and Aβ-mediated ROS-induced toxicity [187,188]. In HD, there is a dysfunction of the mitochondrial complex II, causing an increase in ROS [48]. In the initial phase of HD, the treatment with an Nrf2 agonist leads to an increase of vital cytoprotective genes via the Keap1–Nrf2–ARE in astrocytes and microglia [189].
Activation of the Keap1–Nrf2–ARE pathway by small molecules in astrocytes accelerates the resistance of neurons to non-excitotoxic glutamate toxicity [46–48].
Altered mitochondria function, biogenesis, and mitophagy are important pathological features in PD, and Nrf2 is an important transcription factor that regulates mitochondrial quality control and homeostasis [190]. In PD, there is an activation of the Nrf2–ARE system [191,192] and its pharmacological activation prevents PD progression [49,50].
Nrf2 activation plays a protective role against ROS and cell death caused by the superoxide dismutase 1 (SOD1) mutant protein. In addition, the astrocyte Nrf2 overexpression increases the survival of the SC MNs and extends lifespan in SOD1 transgenic mice [51,52].
Besides, the crosstalk between p62 and the Keap1–Nrf2 pathway in the context of autophagy may play an important role in the removal of ROS, preventing oxidative damage and modulating ER stress during cerebral ischemia-reperfusion injury [53].
Lastly, mitochondria drive neuronal survival, because they sense internal and external death initiators, triggering signaling cascades that converge at the mitochondria and then re-diverge into one or more cell death pathways that lead to a different type of cell death (such as intrinsic apoptosis) [193].
4. Targeting Systemic Modulation
4.1. Caloric Restriction
Caloric restriction (CR) extends lifespan in different organisms and has protective effects on several organs. CR impacts the whole organism: from the systemic milieu to different subcellular populations.
In 2010, Kromer and collaborators suggested that CR benefits are dependent on SIRT1-dependent autophagy [194]. On the other side, it has been pointed out that CR is neuroprotective in PD disease by a ghrelin-AMPK axis, with AMPK being a key inducer of autophagy [195].
Given the obvious impossibility of maintaining a long-term CR, therapeutic interest was raised in discovering novel CR "mimetics" (CRM), which mimics the physiological effects of CR in the organism [196]. Both CR and CR-mimetics have probed efficacy in AD rat models by improving cognitive function through autophagy induction [197], so they are novel therapeutic avenues for treating neurodegeneration.
4.2. Exercise
Physical exercise is gaining interest due to its ability to reduce pathophysiological conditions such as neuropathic pain or improve functional outcomes in stroke models [198].
It also slows down PD progression by the inhibition of the inflammatory reaction and the enhancement of antioxidant balance [199]. It is described that exercise acts by increasing endogenous levels of neurotrophic factors [200,201].
Moreover, it modulates muscle hormone secretion, promoting protective effects in the brain, neurogenesis, and ameliorating brain aging [202]. It has been recently described that the same hormone, irisin, has a role in bone formation [203], indicating that exercise impacts the whole body.
5. Finding Effective Neuroprotectant: What There Is and Where We Go
Common hallmarks of neurodegenerative diseases are a non-correct activation of UPR, the accumulation of autophagic processes, a mitochondrial well-function failure, among others. Altogether, they will overwhelm neurons, provoking their demise.
An effective neuroprotectant must correct these mechanisms by boosting the cell with complete resilience to aging/insults. We need to completely modify the molecular network within the cell, pushing it towards a complete restoration of functions.
Approved drugs such as Riluzole for ALS [204], or clinical trials, like Rapamycin for ALS [204], Spermidine, and DH for AD [205,206], only target one of these degenerative processes, and the neuron is overwhelmed by the other ones. Although they may yield beneficial effects, we propose to find a genetic or pharmacological approach to endorse different molecular pathways- multitarget therapy-instead of only one target.
Specific overexpression of certain proteins such as SIRT1, BIP, and/or ATG5 facilitates neuronal survival after nerve injury, and they neuroprotect in neurodegenerative diseases.
They mainly fine-tune UPR or autophagy networks. SIRT1 activation by the use of transgenic mice or viral vectors demonstrated protection in different neurodegenerative diseases such as ALS, AD, and HD [207–209] and also after nerve injury [55].
SIRT1 deacetylase activity endorses different endogenous mechanisms of protection: autophagy modulates UPR by attenuating PERK increases ATF6 cleavage [23,210], has anti-apoptotic effects, and modulates AKT activity to inhibit anoikis [211,212].
Therefore, the precise modulation of it may enhance cellular resilience. From our recent study, we conclude that modulating SIRT1 deacetylase activity is an essential node for the molecular network to achieve cellular resilience [54,55]. Lastly, BIP overexpression protects against aggregates and induces autophagy and mitophagy [99], so its modulation is also an effective approach to cluster different neuroprotective pathways.
6. Concluding Remarks
Boosting endogenous mechanisms of neuroprotection opens exciting therapeutic avenues to treat neurodegenerative diseases or maintain tissue homeostasis after neurotrauma. Although this is an unexplored field nowadays, it may promote more effective biomedical results than blocking a concrete pathophysiological hallmark.
Therefore, endorsing them by genetic, pharmacological, or systemic-modulation therapies can delay pathology progression and enhance functional recovery. The optimal therapeutic strategy must involve a concrete modulation of the endogenous mechanisms of protection to re-model the complete network and achieve protection.
Author Contributions: D.R.-G. and S.M.-M.-A. wrote the manuscript and C.C. made a critical review. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing does not apply to this article.
Conflicts of Interest: The authors declare no conflict of interest.
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