Abstract

HYPOXIA-INDUCED NEUROTOXICITY: BRIDGING ALPHA-SYNUCLEIN AGGREGATION AND MITOCHONDRIAL DYSFUNCTION IN PARKINSON’S DISEASE

Roshani Rajendra Bhavsar*, Manali Milind Bhide, Shiwani, Ankita chandrakant Shinde, Srushti Gurunath Pirankar and Gadhave Sahil Uttam

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative disorder with progressive motor dysfunction, including tremor, rigidity, and bradykinesia, and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The consequent neuron loss leads to striatal dopamine depletion and secondary motor dysfunction. Alpha-synuclein aggregation and mitochondrial function have been at the forefront of the pathogenic processes most important to PD. Alpha-synuclein is a synaptic neuronal protein that, under pathologic conditions, can misfold and aggregate to form Lewy bodies, hallmarks of PD pathology. In parallel, mitochondrial dysfunction is also responsible for the causation of energy deficits, oxidative stress, and apoptosis, which collectively enhance the vulnerability of neurons. Growing evidence indicates hypoxia as a strong inducer of neurodegeneration in PD through interference with these pathologic features. Hypoxia, or tissue oxygen deficiency, can result from aging, vascular compromise, respiratory distress, or environmental trauma. Hypoxia in the central nervous system produces many pathologic effects including oxidative stress, inflammation, and cellular energy homeostasis disruption. These factors have a direct impact on the alpha-synuclein misfolding and aggregation and mitochondrial bioenergetics and dynamics. Recent research has indicated that hypoxia increases the expression of hypoxia-inducible factors (HIFs), including HIF-1α, which induce transcriptional cascades that reorganize mitochondrial function, regulate protein degradation pathways, and regulate neuroinflammatory processes. Furthermore, chronic or intermittent hypoxia can induce a condition of hypometabolism in neurons, rendering them vulnerable to the toxic effects of aggregated proteins and dysfunctional organelles This review describes how hypoxia induces alpha-synuclein misfolding and aggregation through oxidative modification, defective proteostasis, and inflammatory expression-driven. This review also assesses how hypoxic stress enhances mitochondrial impairment through dysregulation of mitochondrial dynamics, decreased ATP synthesis, and increased production of reactive oxygen species (ROS). Finally, the synergistic effect of these pathological processes leads to neuronal apoptosis and neurodegeneration. Elucidation of this tripartite interaction between hypoxia, alpha-synuclein pathology, and mitochondrial dysfunction has the potential to reveal new therapeutic approaches against hypoxia-mediated mechanisms in PD. These could include the delivery of pharmacological agents to stabilize mitochondrial function, mitigate oxidative damage, suppress pathological protein aggregation, or modulate HIF signaling to restore cellular homeostasis. Elucidation of these interlinked mechanisms may provide a window of opportunity for the development of disease-modifying therapies for Parkinson's disease.

Keywords: Parkinson’s disease, hypoxia, alpha-synuclein, mitochondrial dysfunction, neurotoxicity, oxidative stress, HIF-1?.