Introduction

Neurodegenerative disorders, such as Alzheimerâ??s disease, Parkinsonâ??s disease, Huntingtonâ??s disease and amyotrophic lateral sclerosis, are characterized by the progressive loss of neuronal structure and function, leading to severe cognitive and motor impairments. At the molecular level, these conditions share common pathological features, including protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, impaired autophagy and neuroinflammation. Genetic mutations, epigenetic alterations and disrupted cellular signaling pathways further exacerbate neuronal vulnerability and accelerate disease progression. Understanding these molecular mechanisms not only provides insight into the pathogenesis of neurodegeneration but also opens avenues for potential therapeutic interventions aimed at modulating protein homeostasis, enhancing mitochondrial health, reducing oxidative damage and targeting neuroinflammatory responses [1].

Description

Neurodegenerative disorders are a heterogeneous group of conditions defined by the gradual and irreversible loss of neurons in specific regions of the brain and spinal cord. Despite differences in their clinical manifestations, these disorders often share overlapping molecular hallmarks that drive disease progression. Protein aggregation is one of the most prominent features, as seen with amyloid-β and tau in Alzheimerâ??s disease, α-synuclein in Parkinsonâ??s disease, huntingtin in Huntingtonâ??s disease and TDP-43 in amyotrophic lateral sclerosis. These misfolded proteins form toxic oligomers and insoluble aggregates that disrupt synaptic transmission, impair intracellular trafficking and trigger neuronal death. In addition, impaired proteostasis due to dysfunction of the ubiquitin-proteasome system and autophagy-lysosomal pathway exacerbates protein accumulation. Mitochondrial dysfunction further compounds these effects by reducing ATP availability and increasing reactive oxygen species production. Oxidative stress damages proteins, lipids and DNA, creating a cycle of cellular injury that accelerates neurodegeneration.

Understanding these shared mechanisms is critical for identifying therapeutic targets that may benefit multiple disorders [2].

Protein misfolding and aggregation arise from both genetic mutations and environmental stressors that destabilize protein structure and clearance. In Alzheimerâ??s disease, mutations in APP, PSEN1, or PSEN2 genes increase amyloidogenic processing, leading to the accumulation of amyloid-β plaques. Similarly, hyperphosphorylation of tau promotes neurofibrillary tangle formation, disrupting microtubule stability and axonal transport. In Parkinsonâ??s disease, mutations in SNCA, LRRK2 and PARK2 genes alter α-synuclein folding and clearance, resulting in Lewy body pathology. Huntingtonâ??s disease is caused by CAG repeat expansion in the HTT gene, which produces mutant huntingtin with polyglutamine stretches that aggregate and impair cellular function. Failure of molecular chaperones and proteolytic systems to resolve these aggregates worsens the toxic burden. The prion-like propagation of misfolded proteins between neurons amplifies pathology across interconnected brain regions. These insights highlight the central role of protein aggregation in disease progression and the need for therapies that enhance protein quality control mechanisms [3].

Mitochondrial dysfunction is another central feature of neurodegenerative diseases, contributing to both energy deficits and oxidative stress. Neurons are highly energy-dependent and disruptions in oxidative phosphorylation can severely impair synaptic transmission and plasticity. In Alzheimerâ??s disease, amyloid-β interacts with mitochondrial membranes, impairing electron transport chain function and promoting free radical generation. In Parkinsonâ??s disease, mutations in PINK1 and PARK2 impair mitophagy, allowing dysfunctional mitochondria to accumulate. Complex I inhibition by environmental toxins such as MPTP also provides evidence of mitochondrial vulnerability in Parkinsonâ??s pathogenesis. Reactive oxygen species generated by dysfunctional mitochondria damage proteins, lipids and nucleic acids, exacerbating neuronal degeneration. Excess calcium influx, combined with mitochondrial impairment, amplifies oxidative injury and activates apoptotic pathways. Therapeutic strategies aimed at improving mitochondrial function, such as coenzyme Q10, creatine supplementation and pharmacological enhancers of mitophagy, are under investigation. These findings reinforce the pivotal role of mitochondria as both targets and mediators of neurodegenerative pathology [4].

Given the complexity of neurodegenerative disorders, effective therapeutic interventions must target multiple pathways simultaneously. Current strategies include reducing protein aggregation, enhancing mitochondrial function, modulating neuroinflammation and promoting neuronal survival through neurotrophic support. Small molecules, antibodies and gene therapies are being developed to block amyloid-β or α-synuclein aggregation. Enhancing proteostasis through chaperone upregulation and autophagy activation also holds promise. Approaches to improve mitochondrial health include antioxidants, mitophagy enhancers and metabolic modulators. Although challenges remain due to disease heterogeneity and the blood-brain barrier, advances in molecular neuroscience continue to open new avenues for treatment. Ultimately, a combination of precision medicine and multi-targeted approaches may hold the key to slowing or preventing Neurodegeneration [5].

Conclusion

Neurodegenerative disorders remain among the most challenging conditions in medicine, largely due to their multifactorial molecular basis and progressive nature. The convergence of pathways such as protein misfolding, mitochondrial dysfunction, oxidative stress, excitotoxicity and neuroinflammation highlights the interconnectedness of neuronal injury processes. While each disorder presents unique molecular signatures, the shared mechanisms offer opportunities for broad therapeutic targeting. Advances in genomics, proteomics and neuroimaging are providing deeper insights into disease pathogenesis, enabling early detection and personalized approaches to intervention. However, the complexity of these disorders underscores that single-target therapies are unlikely to yield significant benefits. Instead, a combination of strategies that simultaneously address multiple molecular pathways may offer the most promising outcomes.

Acknowledgment

None.

Conflict of Interest

None.

Reference

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