Will you live to 120? · Folding and Falling Apart

The diseases we fear

Deeper Water — the two disposal routes, and why neurons are doomed to lose. It’s worth understanding why the cell maintains two separate destruction systems, and why one kind of cell is especially helpless. The ubiquitin-proteasome system and autophagy are specialized for different cargo. The proteasome handles soluble, individual proteins, tagged one at a time with ubiquitin and threaded into a narrow barrel — it physically cannot accept anything large or already clumped. Autophagy handles exactly what the proteasome can’t: bulky aggregates, protein clumps, and whole organelles, swallowed wholesale. There is even a third, hybrid route — chaperone-mediated autophagy — in which chaperones ferry specific proteins one by one directly across the lysosome membrane. The redundancy is the point: different threats need different disposal. Now consider the predicament of a neuron. Most cells, when they accumulate damaged proteins, have an escape hatch unavailable to neurons: they divide, and each division halves the concentration of junk between two daughter cells — dilution as a cleanup strategy. But the neurons in your brain are post-mitotic: with rare exceptions they never divide again after you’re young. The neuron you are using to read this sentence is, very likely, as old as you are. It cannot dilute its aggregates by dividing; it can only clear them in place, with crews that weaken over decades. So a neuron is a long-lived cell that depends entirely on its proteostasis crews, for a lifetime, with no fallback — which is precisely why the diseases of protein aggregation are, overwhelmingly, diseases of the aging brain. The most irreplaceable cells we have are the ones least able to take out their own trash.*

The diseases we fear

This brings us to the most frightening corner of aging biology, and the one where honesty matters most, because these are the diseases that take our parents and that we fear for ourselves. Mechanistically, the major neurodegenerative diseases of aging are, at their core, diseases of protein misfolding and aggregation — the cleanup crews losing, in specific cells, to specific proteins.

In Alzheimer’s disease, two proteins aggregate: fragments called amyloid-beta pile up into plaques outside neurons, and a protein called tau twists into tangles inside them. In Parkinson’s disease, a protein called alpha-synuclein aggregates into clumps in the neurons that control movement. In Huntington’s disease — the clearest case of all, because it is purely genetic — an inherited mutation lengthens a repetitive stretch of the huntingtin protein, and the elongated protein aggregates; the longer the inherited repeat, the earlier the disease strikes, a dose-response written into the genome. In ALS and related disorders, still other proteins (TDP-43 among them) misfold and clump. Different protein, different cell type, different symptoms — but the same underlying failure: a protein adopts the wrong shape, the wrong shapes stick together, the aggregates accumulate faster than the aging crews can clear them, and the affected neurons sicken and die.

Many of these aggregates share a common structural endpoint called amyloid — a particular, extremely stable way for misfolded proteins to stack together into fibers. And the most unsettling discovery about aggregation is that it can spread in a self-templating way. The principle was established with prions, the protein-only infectious agents behind mad cow disease and its human counterparts — an idea so radical when proposed (a protein, with no genes, that could be infectious?) that it was widely dismissed before it won a Nobel Prize. A prion is a misfolded protein that, on contact, induces correctly folded copies of the same protein to misfold like it — a bad shape that propagates itself, converting its neighbors. We now know that this seeding behavior is not unique to prions: amyloid-beta, tau, and alpha-synuclein can all seed their own misfolding in this prion-like way and spread the aggregation from neuron to neuron, which helps explain how these diseases march through the brain along predictable routes. The wrong shape is, in a real sense, contagious from molecule to molecule.

Deeper Water — why amyloid is so stable, and why a shape can be contagious. Amyloid is not a random clump; it is a highly ordered structure, in which the protein chains line up side by side into long, flat, ribbon-like sheets (called cross-β sheets), stacked into fibers held together by a dense web of hydrogen bonds. This architecture is extraordinarily stable — more stable, often, than the protein’s own correctly folded shape — which is exactly why it is so hard for the cleanup crews to take apart and why, once formed, amyloid tends to persist. It is also why so many different proteins, with no sequence in common, can all end up as amyloid: the cross-β structure is a kind of generic low-energy basin that almost any protein chain can fall into if it misfolds, a deep secondary well in the folding landscape from the start of the chapter. The self-templating — the “contagious shape” — follows from the structure too. An amyloid fiber has an exposed growing end, and a soluble protein of the same kind that bumps into that end is coaxed to add itself on in the same cross-β arrangement, extending the fiber. Each newly recruited molecule becomes a new template surface. This is why aggregation, once seeded, is autocatalytic: the product of misfolding is itself a catalyst for more misfolding. It is the same logic as a crystal growing in a supersaturated solution — and it is why a tiny seed of aggregate, or in the case of prions a tiny infectious dose, can eventually convert a vast amount of protein.*

Thirty years chasing a plaque

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