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How does mitochondria become a potential trigger for Parkinson's disease?
Parkinson's disease (PD) is a progressive neurodegenerative disease whose root cause is the death of dopaminergic neurons, which is mainly due to changes in biological activity in the brain.Although multiple mechanisms have been proposed to explain neuronal death in PD, some of them are still unknown, especially those related to mitochondrial abnormalities.
Five major neuronal death mechanisms have been proposed, including protein aggregation, disruption of cell autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation and disruption of the blood-brain barrier (BBB).These mechanisms combined may become a key factor in the further worsening of Parkinson's disease.
The first major neuronal death mechanism is protein aggregation.In the brains of Parkinson's patients, the aggregation of alpha-synuclein forms Lewy bodies, which is considered one of the pathological markers of Parkinson's disease.
Although the presence of Lewy bodies is known, recent studies have shown that these aggregations are not the root cause of death but may be the trigger for other linkage effects.With the development of the disease, Lewy bodies first appeared in the olfactory bulb and brain radiated, and eventually accumulated in areas where dopaminergic neurons are concentrated, leading to a vicious cycle of neuronal death.
The second mechanism is the interruption of autophagy.Autophagy is the process in which internal components of cells are degraded and recycled, and is crucial for maintaining cellular function.In Parkinson's disease, abnormal autophagy mechanisms may lead to mitochondria degradation that cannot proceed normally, further aggravating neuronal damage.
Study shows that autophagy dysfunction is associated with many neurodegenerative diseases, including Parkinson's disease, which causes related cellular function regulation to be imbalanced and accelerates neuronal death.
The third main mechanism involves the production of cellular energy, namely the function of mitochondria.Mitochondrial dysfunction can hinder energy production and ultimately lead to neuronal death.This mechanism mainly involves PINK1 and Parkin complexes, which are responsible for mitophagy.
PINK1 is a protein that is usually transported into the mitochondria, and when the mitochondria are damaged, PINK1 accumulates on its surface and recruits Parkin to begin destroying the damaged mitochondria.Studies have shown that age-related mitochondrial DNA mutations increase vulnerability to this death mechanism, thereby accelerating neuronal apoptosis.
As age, mitochondria gradually lose the ability to remove reactive oxygen species (ROS), but still produces ROS, resulting in excessive ROS produced and cell death.The relationship between these oxidative stress and neuronal death suggests the interaction of multiple pathological processes.
The fourth mechanism is neuroinflammation.Microglia are inherent immune cells of the central nervous system and play an important role in the response to nerve damage.Chronic neuroinflammation can lead to tissue degeneration and the destruction of BBB, further aggravating neuronal death.
In Parkinson's disease, microglia cells enter a pro-inflammatory state, and the released factors can cause the death of motor neurons and may form a positive feedback loop, resulting in more cell death.
The fifth mechanism is the destruction of the blood-brain barrier, which may lead to the entry of harmful molecules and alter the function of neurons.In Parkinson's disease, this process can lead to enhanced neuronal apoptosis or death behavior.
The interaction between these various mechanisms may bring about a series of effects, which are ultimately manifested in the patient's motor ability.The death of dopaminergic neurons can lead to motor control disorders, showing typical gaits in Parkinson's patients, such as hunchback, slow walking and trembling.
In all these complex mechanisms, mitochondrial aberrations appear to be one of the potential detonations that lead to neuronal death.This has also attracted the attention of the scientific community. Is it possible to open up new therapeutic paths by repairing or protecting mitochondria?
