Molecular Mechanisms of Dopaminergic Neuron Degeneration in Parkinson's disease: A Comprehensive Review.
Comprehensive review summarizing molecular drivers of dopaminergic neuron loss in PD—α-synuclein aggregation, lysosomal/chaperone-mediated autophagy failure, mitochondrial dysfunction, calcium dysregulation, apoptosis and ferroptosis—and discussing therapeutic approaches such as mitochondrial…
What the AI sees
Comprehensive review summarizing molecular drivers of dopaminergic neuron loss in PD—α-synuclein aggregation, lysosomal/chaperone-mediated autophagy failure, mitochondrial dysfunction, calcium dysregulation, apoptosis and ferroptosis—and discussing therapeutic approaches such as mitochondrial…
Research significance
By synthesizing multiple high-priority, druggable mechanisms (mitochondria, α-synuclein/lysosomal clearance, autophagy, ferroptosis) and mapping them to potential interventions, the review is a useful resource for prioritizing therapeutic targets and repurposing strategies even though it presents…
Source abstract
Parkinson's disease (PD) is a neurological condition that starts with the degeneration of neurons. Neurons play a crucial role in producing dopamine (DA), a type of neurotransmitter that primarily regulates bodily functions such as motor control, posture, motivation, reward, pleasure, cognition, and memory. Other variables that contribute to the disorder include the buildup of Lewy bodies and Lewy neurites, which are composed of increased α-synuclein (α-syn). Depletion of DA in the striatal area and the death of DA-producing neurons are often considered the basis for the mo-tor impairments seen in PD. In addition, both genetic and environmental factors may play a role in PD etiology; specifically, genetic variations and exposure to toxins may contribute to the development of brain lesions. The article aims to outline the current state of knowledge on the dopaminergic pathway and how PD affects DA homeostasis. Various molecular mechanisms are involved in the pathogenesis of PD, including α-syn aggregation, lysosomal and chaperone-mediated autophagy, mitochondrial dysfunction, and abnormal regulation of calcium homeostasis. Intrinsic and extrinsic caspase-mediated apoptosis, autophagic cell death, and ferroptosis are also involved in neurodegen-eration that often leads to PD. The occurrence of PD can be controlled by the inclusion of antioxi-dants, such as mitoquinone, which inhibit mitochondrial oxidative damage, as well as modulation of autophagy, proteostasis, gene therapy, and its editing, and stem cell regeneration. Diverse mechanistic pathogenesis and genetic variations make PD a complicated disease to tackle. Potential treatment approaches, such as modulating autophagy-lysosomal pathways and protecting mitochon-dria, may be better understood with deeper insight into these mechanisms. We conclude by highlighting current and upcoming gene and cell therapies.