Neurometabolite, myo-inositol, induces conformational distortion with enhanced aggregation of Carbonic Anhydrase: Implications for altered metabolite levels in Alzheimer's disease

Metabolite homeostasis is an important component of cellular homeostasis, wherein metabolites play a key role in maintaining the proteostasis of a cell. Alterations in metabolite levels are increasingly observed in several pathological conditions such as protein aggregation disorders including Alzheimer's and Parkinson's disease. In this context, myo-inositol (MI), an important neurometabolite, is found to exhibit elevated concentration of up to 10 mM in Alzheimer's disease (AD). We investigated how MI affects the overall conformational integrity and aggregation propensity of carbonic anhydrase (CA), an important protein with significant implications for cerebrovascular changes during AD. It was observed that MI enhances aggregation propensity of CA by binding to it, resulting in a significant conformational distortion including beta-sheet formation, alterations in hydrogen bonding network and increased exposure of hydrophobic patches. Moreover, MI-induced CA aggregates exhibited amorphous and branched morphology, lacking any directionality or long-range order. Since inhibitors of CA generally are typically effective in preventing amyloid β (Aβ)-induced cellular dysfunction, the findings suggest that MI-induced CA aggregation, at least under in vitro conditions, could potentially accelerate Aβ plaque formation associated with pre-symptomatic cerebrovascular dysfunction in Alzheimer's patients. Future studies are highly warranted to validate the long-term safety and efficacy of MI and its derivatives, commonly used as supplements for conditions like anxiety, depression, diabetes, and compulsive disorders.