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Global Translational Medicine Influence of ferroptosis in neurological diseases

and severe peroxidation of membrane phospholipids factors related to AD have been linked to ferroptosis.
that are rich in polyunsaturated fatty acids (primarily Firstly, iron dysregulation appears to play a key role. Iron
of arachidonic or adrenic acids from phosphatidyl is essential for normal brain function, but abnormal iron
ethanolamine molecules). This process contributes to the accumulation or distribution can lead to oxidative stress
formation of extremely reactive free radicals [1,2] . and neuronal damage . In AD, increased iron levels
[10]
Being a redox-active metal, iron plays an important have been observed in specific brain regions, and this iron
[11]
role in the cellular metabolism of the central nervous dysregulation can promote the occurrence of ferroptosis .
system (CNS). However, the CNS is highly susceptible to Second, lipid peroxidation is also a primal factor.
oxidative damage induced by excess iron accumulation. Ferroptosis involves the peroxidation of polyunsaturated
The correlation between the accumulation of brain iron fatty acids, leading to the production of lipid peroxides and
[12]
and the progression of neurological disorders along with subsequent cell membrane damage . Lipid peroxidation
cognitive decline substantiates ferroptosis as the main form has been detected in the brain of AD patients, suggesting
of cell death in pathophysiological neurodegeneration. a potential link between ferroptosis and neuronal damage
[13]
Ferroptosis is associated with the accumulation of brain in the disease . In addition, depletion of glutathione
[14]
iron, glutathione depletion, and lipid peroxidation, levels has been observed in the brain of AD patients .
leading to functional and cognitive impairment, as well Glutathione depletion can impair the cells’ ability to
as progressive degeneration and death of nerve cells . defend against oxidative damage, making them more
[3]
[15]
Recent studies on ferroptosis have clearly demonstrated susceptible to ferroptosis . Finally, neuroinflammation,
the direct association between free iron, oxidative stress, characterized by the activation of microglia and the
lipid peroxidation, and neuronal cell death, suggesting release of pro-inflammatory factors, is a common feature
[16]
a programmed cell death caused by the accumulation of of AD . Inflammatory processes can induce ferroptosis
iron-dependent lipid reactive oxygen species (L-ROS) . by promoting the accumulation of iron and ROS while
[4]
[15]
Dysfunction in iron metabolism, such as impaired iron reducing antioxidant defenses .
uptake by transferrin receptor (TFRC), compromised PD is one of the most prevalent neurodegenerative
iron export by ferroportin, and disrupted iron storage in conditions. It is characterized by the gradual loss of
ferritin, causes L-ROS production, further resulting in dopaminergic neurons in the substantia nigra pars
ferroptosis . compacta and the development of Lewy bodies and Lewy
[5]
Iron abundance, lipid peroxidation levels, and changes neurites, which are two important pathogenic features of PD.
in glutathione peroxidase 4 activity are the most critical The main protein involved in Lewy disease is α-synuclein,
[17]
indicators of ferroptosis [5,6] . The modulation of ferroptosis which is misfolded and aggregated . The pathogenesis
in neurodegenerative illnesses has been linked to a of PD depends heavily on both iron dyshomeostasis and
number of genetic and epigenetic variables. For instance, glial cell activation, which act as “partners in crime,”
mutations in genes encoding proteins involved in lipid mutually impacting each other and accelerating the
peroxidation and iron metabolism have been associated degradation of dopaminergic neurons [18,19] . Activated
with neurological disorders. This newly discovered cell glia promotes iron dyshomeostasis, leading to stronger
[20]
death mechanism is regulated by several genes related microglial activation . These findings suggest that the
to iron metabolism, including TFRC, divalent metal pathophysiology of PD may be related to the link between
transporter 1, ferritin heavy chain 1, nuclear receptor ferroptosis, glia activation, and neurodegeneration.
coactivator 4, and iron response element binding protein While these observations suggest a potential
2 [7,8] . Moreover, it can be regulated by several pathways, association of ferroptosis with Alzheimer’s and PDs, it is
such as system x , voltage-dependent anion channels, p53, important to note that the exact role and contribution of
-
c
p62-Keap1-Nrf2, and others. Experimental use of iron ferroptosis to the development and progression of both
chelators and several antioxidants has demonstrated their diseases are still areas of ongoing research. Further studies
effectiveness in interrupting the process of ferroptosis and are needed to fully elucidate the complex mechanisms
addressing neurodegenerative diseases . However, further underlying the relationship between ferroptosis and
[3]
exploration of the regulatory mechanisms underlying these neurodegenerative diseases. In this study, we have
ferroptosis is needed to advance the prevention and unraveled the regulatory pathways that might be controlled
treatment of neurological diseases. by ferroptotic transcription factors (FerrTFs) during the
In the context of AD, ferroptosis has been implicated progression of neurodegenerative diseases, such as AD
in neuronal cell death and neuroinflammation, both of and PD. In addition, we have devised potential therapeutic
which are associated with disease progression . Several measures against them.
[9]

Volume 2 Issue 3 (2023) 2 https://doi.org/10.36922/gtm.0318