Proteostasis · Grey Matter

Proteostasis is the cell's upkeep of its proteins (folding them correctly, refolding or destroying the damaged ones and clearing aggregates), and in neurons, which must last a lifetime without dividing, its slow failure is the common ground of the major neurodegenerative diseases.

Proteostasis. Proteostasis is the cell's upkeep of its proteins (folding them correctly, refolding or destroying the damaged ones and clearing aggregates), and in neurons, which must last a lifetime without dividing, its slow failure is the common ground of the major neurodegenerative diseases.

Three systems do the work. Chaperones bind newly made or damaged proteins and help them fold, recognising exposed water-repelling stretches that should be buried inside. The ubiquitin-proteasome system tags proteins for destruction and breaks them down in a barrel-shaped protease, using ATP. Autophagy wraps larger debris (aggregates, worn-out mitochondria) in membranes and digests them in lysosomes. A neuron is unusually exposed: it cannot dilute its damage by dividing, it keeps its synapses far from the cell body where most proteins are made, and it lives for decades.

When clearance falls behind, proteins aggregate. Tau and amyloid beta in Alzheimer's disease, alpha-synuclein in Parkinson's disease, huntingtin in Huntington's disease and misfolded prion protein all form aggregates, and some of them seed further misfolding from cell to cell.

Temperature and pH act on the same weak bonds. The shapes of proteins, including channels, depend on hydrogen bonds and charges, so warming speeds most channel kinetics two- to threefold per 10 °C and, beyond a point, unfolds proteins; acidity changes charges on channels and receptors, and both shift neuronal excitability (fever lowers seizure thresholds in young children).

Proteostasis costs energy. Chaperones and the proteasome consume ATP, so energy failure and protein failure aggravate each other.

A neuron has to maintain one set of machinery for a lifetime.

What would be routine turnover in a dividing cell becomes, over decades, the slow accumulation behind neurodegeneration.

Questions: Why are neurons especially vulnerable to misfolded proteins? Most cells dilute damaged proteins by dividing, but neurons do not divide and must keep the same cell working for decades, so whatever their chaperones, proteasomes and autophagy fail to clear accumulates. Their shape adds strain: synapses lie up to a metre from the cell body where most proteins are made, so repair and disposal depend on long-distance transport along the axon. Their energy budget is tight, and protein quality control itself consumes ATP. Aggregates of tau, amyloid beta, alpha-synuclein and other proteins that build up this way are the hallmarks of Alzheimer's, Parkinson's and related diseases.