Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which metabolic, inflammatory and proteostatic disturbances converge to drive dopaminergic neuron loss and widespread network failure. In this narrative review, we synthesize clinical, epidemiological and experimental evidence to organize PD pathophysiology around three interconnected metabolic axes: mitochondrial dysfunction and impaired glucose and lipid metabolism; chronic oxidative stress; and glial reprogramming and neuroinflammation, with α-synuclein acting as a central integrator at their interface. We then map how currently available dopaminergic, neuromodulatory and rehabilitative therapies interact with these axes, largely providing downstream symptomatic compensation while leaving core metabolic and inflammatory drivers only partially addressed. Next, we review RNA sequencing (RNA-Seq) and related transcriptomic studies in human brain and peripheral tissues, highlighting convergent differentially expressed genes in mitochondrial, synaptic, immune and proteostasis pathways, as well as major methodological challenges and opportunities for molecular subtyping and biomarker discovery. Together, these lines of evidence support a systems-level view of PD in which α-synuclein–centered metabolic failure and glial dysregulation are key therapeutic targets and in which high-quality RNA-Seq, integrated with advanced bioinformatics, may help define biologically grounded PD endotypes and accelerate the development of truly disease-modifying interventions.
Duarte et al. (Thu,) studied this question.