Opportunities and challenges for molecular chaperone modulation to treat protein-conformational brain diseases

A common pathological hallmark of protein-conformational brain diseases is the formation of disease-specific protein aggregates. In Alzheimer’s disease (AD), these are comprised of Amyloid-β (Aβ) and Tau as opposed to α-synuclein in Parkinson`s disease (PD) and N-terminal fragments of mutant huntingtin (mHTT) in Huntington’s disease (HD). Most aggregates also sequester molecular chaperones, a protein family that assist in folding, re-folding, stabilization and processing of client proteins including misfolded proteins in brain diseases. Molecular chaperone modulation has achieved remarkable therapeutic effects in some cellular and preclinical animal models of protein-conformational diseases. This has raised hope for chaperone-based strategies to combat these diseases. Here, we briefly review the functional diversity and medical significance of molecular chaperones, their therapeutic potential and common and specific challenges towards clinical application