Misfolded Proteins

Misfolded proteins are aberrantly folded proteins that fail to achieve their functional three-dimensional structure. This misfolding disrupts their normal function and often leads to aggregation, which is a hallmark of many neurodegenerative diseases.

• Proteins must fold into specific three-dimensional shapes to perform their biological functions.
• Folding is guided by:
  1. Amino acid sequence (primary structure).
  2. Interactions such as hydrogen bonding, hydrophobic interactions, and ionic bonds.
• Assisted by chaperone proteins to prevent misfolding and aggregation.

1. Genetic Mutations: Single-point mutations can destabilize protein folding (e.g., mutation in SOD1 in ALS).
2. Post-translational Modifications: Aberrant phosphorylation, glycation, or oxidation (e.g., hyperphosphorylated tau in Alzheimer’s).
3. Cellular Stress: Oxidative stress, inflammation, or changes in pH.
4. Aging: Decline in protein quality control mechanisms, including chaperones and proteasomes.

1. Loss of Function: Misfolded proteins cannot perform their normal roles (e.g., prion protein in Creutzfeldt-Jakob disease).
2. Gain of Toxic Function: Misfolded proteins form toxic aggregates that interfere with cellular processes (e.g., beta-amyloid plaques in Alzheimer’s).
3. Aggregation and Inclusion Bodies:
   1. Alzheimer’s disease: Beta-amyloid plaques and tau tangles.
   2. Parkinson’s disease: Alpha-synuclein aggregates (Lewy bodies).
   3. Huntington’s disease: Mutant huntingtin protein aggregates.

• Membrane Damage: Misfolded proteins disrupt cell membranes, causing ion leakage and cellular stress.
• Disruption of Cellular Processes: Inhibit proteasome activity, autophagy, and mitochondrial function.
• Neuroinflammation: Activation of microglia and astrocytes exacerbates damage.

To maintain proteostasis (protein homeostasis), cells employ:

1. Molecular Chaperones: Help proteins fold correctly (e.g., heat shock proteins).
2. Ubiquitin-Proteasome System (UPS): Tags misfolded proteins with ubiquitin for degradation.
3. Autophagy-Lysosomal Pathway: Degrades aggregated proteins and damaged organelles.
4. Endoplasmic Reticulum-Associated Degradation (ERAD): Clears misfolded proteins from the ER.

1. Reducing Misfolding: Chaperone-based therapies (e.g., HSP inducers).
2. Promoting Clearance: Enhancing autophagy or proteasome activity (e.g., ambroxol for Parkinson’s).
3. Preventing Aggregation:
   1. Monoclonal antibodies against misfolded proteins (e.g., lecanemab for beta-amyloid in Alzheimer’s).
4. Small Molecule Stabilizers: Stabilize the native conformation of proteins (e.g., tafamidis for transthyretin amyloidosis).
5. Gene Therapy: Correcting genetic defects.
6. Immunotherapy: Vaccines targeting misfolded proteins to stimulate clearance.

1. Structural Biology: Advanced imaging techniques (e.g., cryo-EM) to study protein aggregates.
2. Artificial Intelligence: Predicting misfolding patterns and designing interventions.
3. Gene Editing: Correcting mutations associated with misfolding (e.g., CRISPR).