The role of ATP in pathological and physiological aggregation

Aggregation is the organization of proteins into higher-ordered structures. This process is essential for many functions relating to normal cell development and activity. However, aggregation can also prove pathological in certain contexts when it arises from protein misfolding, subsequent aberrant interactions, and an eventual toxic aggregate-buildup. This can lead to neurodegenerative diseases, such as Parkinson’s disease (PD) or Alzheimer’s disease (AD). Aging is a primary risk factor for these diseases, as the aging process impedes the ability of our brains to generate ATP (a key energy source) to modulate the refolding or degradation of these aggregates. One approach to mitigate this harmful aggregation is to elevate ATP back to normal levels using the drug Terazosin. This drug is normally prescribed for benign prostate hyperplasia (BPH) but can also increase cellular ATP. However, it is unknown if the elevation of ATP also impedes important physiological aggregates. Using strains that are genetically depleted in ATP, we can study the effects of low ATP as well as the effect of restoring ATP to normal levels using exogenous ATP or ATP elevating drugs such as terazosin. I found: (1) the aggregates implicated in AD and PD reduced after Terazosin treatment. (2) Physiological aggregates were also elevated in an ATP-depleted strain, (3) reduced back to normal levels when ATP was increased, and (4) depleted below physiological levels when ATP was increased beyond normal levels. Overall, I show that ATP is a critical leverage point in regulating both harmful and physiological aggregation. ATP may prove as a useful target to treat neurodegeneration, but it is also important that we continue to understand the relationship between ATP and aggregation involved in normal cellular functions.