Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons. Most neurodegenerative diseases are proteinopathies caused by proteins that fail to fold into their normal configuration (“misfolding”), leading to malfunction and accumulation of toxic proteins. When toxic proteins accumulate inside neurons, they overwhelm the cell’s ability to destroy them, leading to neuronal death and cognitive decline.
Proteinopathies include Alzheimer’s disease (AD), Parkinson’s disease (PD), and rare diseases such as frontotemporal dementia (FTD) and Huntington’s disease (HD). The misfolded toxic Tau protein is a key pathogenic factor in AD and certain FTDs, including primary progressive aphasia (PPA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Misfolded Tau aggregates into neurofibrillary tangles (NFTs) in diseased neurons, which ultimately cause their death. Other misfolded toxic proteins include TDP-43 and Fus in certain FTDs, alpha-Synuclein in PD, Huntingtin in HD, and Abeta in AD. Many of these neurodegenerative diseases are associated with aggregates comprised of multiple proteins that contribute to these proteinopathies.
The Role of Proteostasis in Neurodegenerative Diseases
Proteostasis is the process by which cells regulate proteins – when and how much are made, their folding, assembly, and transport, how they are removed from cells, and how long they survive. In a healthy cell, protein production and removal is in balance. Factors that affect proteostasis include aging, exposure to physiological and environmental stress, and exposure to diseased proteins. Because proteostasis is fundamental to the maintenance of healthy cells, it is not surprising that an imbalance may lead to neurodegenerative diseases, metabolic diseases, or cancer.
A key player in proteostasis is a class of proteins called ‘molecular chaperones’ that are essential for the folding, maintenance and targeting of unwanted proteins. Under normal conditions, chaperones help to maintain a balance between properly folded proteins and degradation and clearance of unwanted or misfolded proteins. In a diseased state, there is an increase in misfolded and aggregated toxic proteins, overwhelming the ability of the chaperone system to maintain equilibrium, and resulting in cell death.
Normal State Diseased State Restored State
Yuma is developing novel disease-modifying oral small molecule drugs neurodegenerative diseases that re-establish balance in protein folding, reduce aggregation and increase removal of toxic proteins in the brain.
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