Misfolded Proteins [Neurosurgery Wiki]

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====== Misfolded Proteins ======
Misfolded [[protein]]s 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 disease]]s.

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

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

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

===== Mechanisms of Toxicity =====
  * **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.

===== Protein Quality Control Systems =====
To maintain proteostasis (protein homeostasis), cells employ:
  - **Molecular Chaperones**: Help proteins fold correctly (e.g., heat shock proteins).
  - **Ubiquitin-Proteasome System (UPS)**: Tags misfolded proteins with ubiquitin for degradation.
  - **Autophagy-Lysosomal Pathway**: Degrades aggregated proteins and damaged organelles.
  - **Endoplasmic Reticulum-Associated Degradation (ERAD)**: Clears misfolded proteins from the ER.

===== Misfolded Protein-Related Neurodegenerative Diseases =====
^ **Disease**          ^ **Misfolded Protein**          ^ **Aggregation Type**            ^
| Alzheimer’s disease  | Beta-amyloid, Tau             | Plaques, Neurofibrillary tangles |
| Parkinson’s disease  | Alpha-synuclein               | Lewy bodies                     |
| Huntington’s disease | Mutant huntingtin             | Polyglutamine inclusions        |
| ALS                  | SOD1, TDP-43, FUS             | Cytoplasmic inclusions          |
| Prion diseases       | Prion protein (PrP^Sc^)       | Amyloid plaques                 |

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

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