Can Existing Mechanisms be Enhanced to Clear Age-Related Protein Aggregates?

Human biochemistry does include systems capable of breaking down or otherwise removing the hyperphosphorylated tau protein deposits observed to be associated with the neurodegenerative conditions known as tauopathies, a class that includes Alzheimer's disease. Obviously, these mechanisms are far from adequate in the normal operation of aged metabolism, but could they be boosted to effectively clear out deposits of broken proteins? That is essentially what is taking place in the development of immunotherapies to clear out β-amyloid and tau in Alzheimer's patients, harnessing the immune system to the task. But are there other, more fundamental approaches that may just involve enhancing the amounts or activities of specific proteins? The research here suggests that this might be the case.

Inside the cell, proteins need to be folded to be functional and active. Molecular chaperones are key enzymes that assist in folding proteins by stabilizing nascent polypeptide chains and by facilitating interactions that help stabilize a final structure. These chaperones also prevent the aggregation of newly formed proteins and can shunt misfolded proteins toward degradation pathways. In addition to interacting with newly synthesized proteins, chaperones also help to maintain cellular homeostasis by triaging toxic protein aggregates, which are responsible for causing neurodegenerative diseases.

Two proteins that can form these toxic aggregates are tau and α-synuclein, which form tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease, respectively. These proteins aggregate to form small, soluble aggregates termed oligomers and long fibrils often termed amyloids, both of which are thought to be toxic. Here we show that a chaperone, cyclophilin 40 (CyP40), interacts with and dissolves tau and α-synuclein aggregates. CyP40 may accomplish this by interacting with proline residues in these proteins, which are known to play a key role in fibril stability. We show that CyP40 both lowers tau fibrils and oligomers in mice that overexpress tau protein and preserves cognition in these transgenic animals.

While being the first human PPIase to display disaggregation activity, CyP40 is not the first disaggregase to be identified. Certain chaperone complexes have been shown to facilitate the disaggregation of oligomers and fibrils. The existence of amyloid disaggregases presents a new avenue for therapeutic strategies. The procognitive effects of CyP40 overexpression in the tauopathic brain suggest that strategies to either induce or deliver disaggregases to the central nervous system could halt or even rescue cognitive deficits associated with neurotoxic amyloids.

Though CyP40 can directly interact with the chaperone heat shock protein Hsp90, the effects described here do not appear to be Hsp90 dependent. Further studies are required to determine if there are endogenous mechanisms to increase CyP40 activity either through the up-regulation of CyP40 expression, by increasing CyP40 stability, or by increasing the enzymatic activity of CyP40. Recent work suggests that upon cellular stress Hsp90 may dissociate from CyP40, leading to an increased pool of more catalytically active CyP40. This may hint at a possible mechanistic pathway by which CyP40 may be "turned on" in response to stress, including toxic amyloid build-up. In addition to CyP40, there are currently 41 known human PPIases within the cyclophilin, FKBP, and parvulin families. Therefore, future screening may reveal additional PPIases with activities similar to CyP40, including disaggregation. Additionally, CyP40 and other PPIases should be further characterized for disaggregation activity against proline-containing amyloids, especially those associated with disease.



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