Unraveling Neurodegeneration: Common Molecular Mechanisms and Novel Therapeutic Concepts in Major Neurodegenerative...

Although Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD) present with markedly different clinical phenotypes, these neurodegenerative diseases (NDDs) appear to converge on a shared set of underlying molecular disturbances. This review sought to integrate disease-specific causative triggers with shared pathogenic pathways, focusing on neuroinflammatory signaling, oxidative imbalance, mitochondrial impairment, and disrupted protein homeostasis, in order to support multi-target, disease-modifying therapeutic strategies.

Relevant classical and contemporary literature, encompassing original research and review articles on the molecular basis of AD, PD, ALS, MS, and HD, was reviewed and synthesized narratively, with attention to how neuroinflammatory and oxidative stress pathways intersect, reinforce one another through mitochondrial and inflammasome-driven feedback, and recur across the five conditions.

In each disorder, persistently activated microglia and astrocytes secreted inflammatory mediators and reactive oxygen species, engaged the NLRP3 inflammasome, and progressively destabilized cellular homeostasis through a self-perpetuating cycle linking neuroinflammation and oxidative stress. Disease-specific lesions nonetheless persisted: amyloid-β and tau pathology in AD; α-synuclein aggregation with iron-driven mitochondrial damage in PD; RNA-binding protein dysfunction, proteostatic collapse, and excitotoxicity in ALS; inflammatory demyelination and axonal bioenergetic failure in MS; and mutant huntingtin-driven transcriptional and mitochondrial disruption in HD. These distinct triggers ultimately converged on shared downstream cascades.

Recognizing this shared pathogenic foundation supports multi-target therapies-such as Nrf2 activation, NLRP3 inhibition, mitochondria-targeted antioxidants, and gene-based interventions-that extend across diagnostic boundaries, though challenges in intervention timing, patient stratification, and clinical translation remain unresolved.