Transmembrane Proteins in Neurodegeneration: Pathophysiology from Alzheimer's to Parkinson's Disease

Neurodegenerative diseases, including Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), represent a growing global health burden due to aging populations. These disorders are characterized by progressive neuronal dysfunction, protein aggregation, synaptic impairment, and neuronal loss. Transmembrane proteins, which regulate signal transduction, material transport, and cell communication, have emerged as key contributors to disease pathogenesis. In AD, amyloid precursor protein processing, N-methyl-D-aspartate receptor overactivation, and microglial receptor signaling drive β-amyloid accumulation, excitotoxicity, and neuroinflammation. In PD, α-synuclein aggregation, dopamine receptor dysregulation, mitochondrial dysfunction, and impaired iron homeostasis disrupt neuronal and synaptic integrity. Despite differences in clinical manifestations, both AD and PD share common mechanisms involving abnormal protein folding, altered calcium signaling, and oxidative and endoplasmic reticulum stress, largely mediated by transmembrane proteins. These shared pathways highlight the interconnected nature of these devastating conditions. These proteins also provide opportunities for therapeutic targeting and biomarker development. Current strategies include secretase inhibitors, N-methyl-D-aspartate receptor modulators, dopamine agonists, and emerging approaches targeting α-synuclein and other misfolded proteins. While challenges remain in achieving selectivity, delivery, and clinical efficacy, advances in molecular biology underscore the potential of transmembrane proteins as critical targets for diagnosis and treatment. Ongoing research continues to unravel their complex roles, and future studies will further elucidate their precise involvement in disease progression, offering hope for new interventions. This comprehensive review summarizes current knowledge on the structural and functional roles of transmembrane proteins in AD and PD, their contributions to shared pathological mechanisms, and their potential as biomarkers and therapeutic targets.