Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a group of progressive neurological disorders marked by the selective loss of neurons.

The burden of these diseases continues to escalate globally, with no definitive cure currently available.

To design effective therapeutic interventions, it is essential to unravel the molecular events that precede and drive neuronal degeneration.

Misfolded Proteins and Proteostasis Collapse

Central to many neurodegenerative conditions is the accumulation of misfolded or aggregated proteins. In Alzheimer's disease, the aggregation of beta-amyloid (Aβ) and hyperphosphorylated tau disrupts neuronal signaling and induces cytotoxicity. Meanwhile, alpha-synuclein aggregates form Lewy bodies in Parkinson's disease.

Recent research by Dr. Dennis Selkoe at Harvard Medical School has emphasized that soluble oligomeric forms of Aβ, rather than large plaques, exhibit the most potent synaptotoxic effects. The misfolded proteins escape the quality-control mechanisms of the ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP), leading to proteostasis failure. Impaired autophagic flux is now recognized as a shared pathological hallmark across multiple neurodegenerative conditions.

Mitochondrial Dysfunction: The Energy Crisis Within

Neurons are highly dependent on mitochondrial integrity for ATP production and calcium buffering. Mitochondrial dysfunction is a key contributor to neuronal death, particularly in Parkinson's disease. Mutations in genes such as PINK1 and Parkin impair mitophagy, the selective removal of damaged mitochondria, resulting in elevated oxidative stress and energy deficits.

A 2024 study in Nature Neuroscience highlighted how the loss of mitochondrial complex I activity precedes motor symptoms in PD patients. The research team, led by Dr. Valina Dawson at Johns Hopkins, demonstrated that mitochondrial-derived vesicles carrying oxidized cargo accumulate in the dopaminergic neurons of the substantia nigra, amplifying neurotoxicity.

Neuroinflammation: Friend Turned Foe

Microglia and astrocytes, the brain's primary immune cells, initially respond to injury and aggregation with protective intent. However, chronic activation transforms this response into a damaging proinflammatory cascade. In ALS, for instance, sustained release of cytokines such as TNF-α and IL-1β accelerates motor neuron degeneration.

Emerging work by Dr. Beth Stevens from Boston Children's Hospital shows that complement protein C1q, released by activated microglia, tags synapses for elimination. Her research implicates aberrant synaptic pruning in the early stages of Alzheimer's disease, even before the appearance of plaques or tangles.

RNA Metabolism and Stress Granule Dynamics

Defects in RNA-binding proteins (RBPs) are increasingly implicated in neurodegeneration. In ALS and frontotemporal dementia (FTD), mutations in TARDBP (encoding TDP-43) and FUS lead to aberrant phase separation and the formation of persistent stress granules. These granules, normally transient structures formed under cellular stress, become pathogenic and interfere with mRNA processing and transport.

A 2023 Cell Reports study revealed that the persistent sequestration of RBPs into stress granules impairs local protein synthesis at synapses, disturbing synaptic plasticity. Therapeutically targeting the liquid–liquid phase separation process holds promise, although clinical translation remains in early stages.

DNA Damage and Impaired Repair Mechanisms

Post-mitotic neurons are especially vulnerable to DNA double-strand breaks (DSBs). In Huntington's disease, expanded CAG repeats in the HTT gene not only lead to mutant huntingtin protein toxicity but also promote genome instability. Studies have confirmed impaired recruitment of repair factors such as ATM and BRCA1, resulting in persistent DNA damage and transcriptional dysregulation.

According to a 2024 review in Neuron by Dr. Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory, restoring chromatin architecture and enhancing DNA repair enzymes might be a viable neuroprotective strategy.

Synaptic Dysfunction: Early Events in Disease Progression

Synaptic loss correlates more strongly with cognitive impairment than plaque load in Alzheimer's disease. Aβ oligomers disrupt NMDA receptor function, calcium homeostasis, and dendritic spine morphology. In PD, altered dopamine release and receptor trafficking compromise cortico-striatal communication, contributing to bradykinesia and cognitive deficits.

Neurophysiological recordings in prodromal AD patients have shown altered theta–gamma coupling in hippocampal circuits—an early marker of synaptic failure. This shift, according to Dr. Michela Gallagher at Johns Hopkins University, precedes detectable memory deficits and offers a window for early intervention.

Therapeutic Implications: Moving Beyond Symptom Control

Current therapies primarily manage symptoms without halting disease progression. Molecular insights are guiding novel approaches such as antisense oligonucleotides (ASOs), gene editing via CRISPR-Cas9, and small molecules targeting proteostasis and mitochondrial dynamics.

The FDA's 2023 approval of tofersen, an ASO therapy targeting SOD1 mutations in ALS, marks a significant shift toward precision medicine in neurodegeneration. While challenges remain in delivery, specificity, and long-term effects, the pipeline of targeted interventions is growing steadily.

Understanding neurodegeneration at the molecular level has revealed an intricate interplay of protein misfolding, mitochondrial failure, immune dysregulation, RNA mishandling, and synaptic instability. These insights are transforming the approach to diagnosis and treatment, bringing hope for disease-modifying therapies. Continued investment in molecular neuroscience, coupled with advanced tools like single-cell transcriptomics and in vivo imaging, promises to illuminate the earliest stages of neuronal decline—and potentially reverse them.