ABSTRACT Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra and widespread involvement of multiple neurotransmitter systems. Traditionally recognized for its motor manifestations including bradykinesia, tremor, rigidity, and postural instability, PD also encompasses an array of non‐motor symptoms including cognitive impairment, neuropsychiatric disturbances, sleep disorders, and autonomic dysfunction. Recent insights have expanded PD pathophysiology beyond dopaminergic deficiency to include α‐synuclein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and gut–brain axis disruption. Growing evidence links insulin resistance and metabolic dysregulation to neuronal vulnerability, suggesting PD as part of a broader metabolic–neurodegenerative continuum. Emerging evidence further indicates that progressive bioenergetic failure, impaired mitochondrial resilience, and disrupted neuronal energy homeostasis may represent central mechanisms linking α‐synuclein aggregation, oxidative stress, neuroinflammation, and multisystem neurodegeneration in PD. This review specifically emphasizes an integrated energy failure–centered framework that connects molecular pathology with clinical heterogeneity and therapeutic vulnerability. Current therapeutic strategies such as levodopa‐based pharmacotherapy, dopamine agonists, MAO‐B/COMT inhibitors, and adjunct agents provide symptomatic relief but fail to modify disease progression. Surgical and device‐assisted interventions such as deep brain stimulation and continuous infusion therapies improve motor control yet remain limited by non‐motor efficacy and invasiveness. Emerging therapies targeting molecular and metabolic pathways, including gene and cell‐based approaches, GLP‐1 receptor agonists, and microbiome modulation, represent promising avenues for neuroprotection and disease modification. This review integrates molecular, metabolic, and clinical insights to emphasize the need for a holistic, multi‐target therapeutic paradigm in advancing the management of PD.
Aijaz et al. (Mon,) studied this question.