Proteinopathy is a term for diseases where proteins become structurally abnormal, disrupting the function of cells and tissues. Proteins must fold into a specific shape to work correctly, much like a key must have the right shape to open a lock. When a protein misfolds, it can no longer perform its job. This misshapen protein might also become actively harmful, interfering with cellular activities and contributing to several progressive neurodegenerative diseases.
The Process of Protein Misfolding
Every protein’s function depends on its unique three-dimensional structure, achieved through a complex folding process. This process is guided by proteins called chaperones, which help newly made proteins fold into their correct shapes. Chaperones also act as quality control, identifying improperly folded proteins and giving them another chance to achieve their correct conformation.
Even with this assistance, some proteins fail to fold correctly. The cell has two primary systems for removing these defective proteins. The ubiquitin-proteasome system (UPS) tags individual misfolded proteins with ubiquitin, which marks the protein for destruction by the proteasome. The proteasome then acts like a cellular recycling center, breaking the protein down into smaller pieces.
For larger clumps of misfolded proteins or damaged organelles, the cell uses autophagy. This mechanism involves engulfing the aggregated proteins in a vesicle, which then fuses with a lysosome containing powerful enzymes that degrade the contents. Genetic mutations, environmental stress, or aging can impair the efficiency of both the UPS and autophagy, causing misfolded proteins to accumulate and setting the stage for cellular damage.
Cellular and Tissue Consequences
The accumulation of misfolded proteins triggers harmful events inside the cell. These abnormal proteins are often sticky, causing them to clump together in a process called aggregation. They first form small, soluble clusters known as oligomers, which are considered highly toxic to neurons. Over time, these oligomers grow into larger, insoluble structures like fibrils, which deposit as plaques or Lewy bodies.
These protein aggregates cause damage in two main ways. A “toxic gain-of-function” occurs when aggregates interfere with cellular processes like energy production. A “loss-of-function” happens when the protein, locked in an aggregate, can no longer perform its normal duties.
This buildup and loss of function puts stress on the cell, activating inflammatory pathways. The combination of toxic gain-of-function, loss-of-function, and chronic inflammation leads to the gradual death of neurons. This cell loss causes brain tissue to shrink, resulting in the functional decline seen in neurodegenerative diseases.
Associated Neurodegenerative Diseases
Different neurodegenerative diseases are defined by the specific protein that misfolds and accumulates. Alzheimer’s disease, the most common form of dementia, is characterized by two proteins: amyloid-beta and tau. Amyloid-beta proteins form plaques outside of neurons, while tau proteins form tangles inside them.
Parkinson’s disease, which affects movement, is linked to the accumulation of the alpha-synuclein protein into aggregates known as Lewy bodies. The loss of neurons containing these bodies is responsible for the tremors and rigidity seen in patients. Huntington’s disease is a genetic disorder where a mutation in the huntingtin protein leads it to misfold and accumulate.
Amyotrophic Lateral Sclerosis (ALS), which causes loss of muscle control, is associated with the aggregation of proteins like TDP-43 and SOD1. Prion diseases, such as Creutzfeldt-Jakob disease, are caused by a misfolded prion protein that induces healthy prion proteins to also misfold, creating a chain reaction. Each of these conditions shows how a specific protein’s aggregation leads to distinct patterns of neurodegeneration.
Diagnosis and Therapeutic Approaches
Diagnosing proteinopathies involves clinical evaluation and advanced imaging. Positron Emission Tomography (PET) scans can visualize specific protein aggregates in the living brain using radioactive tracers that bind to deposits like amyloid-beta or tau. Analysis of biomarkers in cerebrospinal fluid or blood can also provide evidence for a particular neurodegenerative condition.
Current treatments primarily manage symptoms, but research is increasingly aimed at the root cause of proteinopathy. One strategy is to prevent the initial misfolding and aggregation of proteins. This includes developing small molecules that stabilize a protein’s correctly folded state or prevent them from sticking together.
Another avenue is to enhance the brain’s natural protein clearance systems. Researchers are exploring ways to boost the activity of the UPS or autophagy to more effectively remove harmful protein aggregates. Other approaches include immunotherapies, which use antibodies to target and clear specific misfolded proteins. These strategies represent a shift towards therapies designed to modify the course of the disease.