Post-translational modifications in the form of misfolding and aggregation in the form of protein acetylation and Phosphorylation etc can alter in the tertiary structure of protein. These interactions result in a tendency to aggregate and fold on a misguided manner. This results in the accumulation of toxic protein aggregates. These factors ultimately lead to many neurodegenerative diseases.

Protein folding, stability, and function are significantly altered by post-translational modifications (PTMs), which increasingly affect neurodegenerative disease etiology. PTMs gone wrong can disrupt protein homeostasis, fostering misfolding, aggregation, and a loss in practical biology, all of which are familiar symptoms of diseases such as Alzheimer's, Parkinson's, and Huntington's (Walsh & Selkoe, 2007). Phosphorylation is a well-researched PTM area in neurodegeneration. The inherent ability of tau proteins to bind to microtubules is disrupted and aggregation into neurofibrillary tangles is triggered in Alzheimer's disease by tau (Iqbal, Liu, Gong, & Grundke-Iqbal, 2010). This wayward adaptation shifts the conformation of tau for the worst, prompting a dangerous beta-sheet-enriched composition that restricts neuronal function. Ubiquitination is another critical concerning system that affects protein quality and helps us understand PTMs' undeniable impact in the protein quality control area. The accumulation of misshapen proteins by disrupting the ubiquitin-proteasome system— for example, alpha-synuclein in Parkinson's disease, which results in Lewy bodies— leads to consequences. Problems with ubiquitination impede these hazardous compounds' destruction and clearance, making cell stress much worse and triggering neurotoxicity (Wang & Mandelkow, 2016).

Other PTMs, like acetylation, glycation, and sumoylation, impact protein-surface interactivity and bigotry. An illustration is huntingtin protein acetylation affecting its Huntington's disease Aggregation and risk. The unknown potential for cross-linking and insolubility of amyloid-beta peptides in Huntington's disease can be stimulated by glycation (Mishra et al., 2018). Whatever the PTMs, they're Outlined as molecular levers for regulating protein unraveling landscapes and their practical conditions. The failure of these changes impacts protein homeostasis, eliciting neurotoxicity and adding to the succession of diseases. An attractive new neurodegeneration therapy aim is the targeting of bad PTMs. Whatever the PTMs, they're Outlined as molecular levers for regulating protein unraveling landscapes and their practical conditions. The failure of these modifications impacts protein homeostasis, prompting neurotoxicity and cleverly taming disease progression. Targeting the inappropriate message typification thus represents an interesting new neurodegeneration region (Iqbal et al., 2010).

References: Iqbal, K., Liu, F., Gong, C. X., & Grundke-Iqbal, I. (2010). Tau in Alzheimer disease and related tauopathies. Current Alzheimer Research, 7(8), 656-664.

Mishra, S., Tripathi, S., Tripathi, A. K., Singh, A., Singh, S., & Singh, A. K. (2018). Post-translational modifications and protein aggregation: emerging roles in neurodegenerative diseases. Neuroscience Letters, 662, 1-9.

Walsh, D. M., & Selkoe, D. J. (2007). A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nature Reviews Neuroscience, 8(11), 801-812.

Wang, Y., & Mandelkow, E. (2016).Tau in physiology and pathology. Nature Reviews Neuroscience, 17(1), 5-21.

Post-translational modifications (PTMs) are critical drivers of protein dysfunction in neurodegenerative diseases, fundamentally altering both folding pathways and functional outcomes.

Key mechanisms from current research:

1. Phosphorylation-induced structural changes:

• Tau hyperphosphorylation at Ser396/Ser404 disrupts its microtubule-binding domain through electrostatic repulsion
• Creates conformational shifts that expose aggregation-prone regions
• In computational modeling, we observe significant RMSF increases at phosphorylation sites, indicating enhanced local flexibility

2. Ubiquitination dysfunction:

• Impaired ubiquitin-proteasome system leads to accumulation of misfolded proteins
• Failed clearance mechanisms are hallmarks of Parkinson's (α-synuclein) and Alzheimer's (tau tangles)
• Ubiquitination sites often coincide with regions prone to pathological aggregation

3. Disease-specific examples:

• Alzheimer's: Tau hyperphosphorylation destabilizes native structure, promoting neurofibrillary tangle formation
• Parkinson's: α-synuclein phosphorylation at Ser129 (found in ~90% of Lewy bodies) alters aggregation kinetics
• ALS: SOD1 modifications affect copper/zinc binding, compromising enzymatic function

Computational insights:From molecular dynamics perspectives, PTMs typically:

• Alter electrostatic surface potentials
• Disrupt native hydrogen bonding networks
• Shift conformational energy landscapes toward misfolded states
• Change protein-protein interaction affinities

Therapeutic relevance:Understanding PTM effects is crucial for designing interventions. For instance, in my current work on NMDA receptor modulators for Alzheimer's, we consider how receptor phosphorylation states might affect allosteric binding sites.

The cascade from PTM → misfolding → aggregation → neurodegeneration represents a key pathway where computational approaches can guide therapeutic strategies.