Neurodegeneration: the protein table
- Topic
Most neurodegenerative diseases share one theme: a misfolded protein clumps inside or outside neurons and spreads through connected circuits.
What it is
Neurodegenerative diseases cause slow, selective loss of groups of neurons that share function. Most are defined by an aggregated protein that the pathologist sees as an inclusion or deposit. Misfolded proteins resist clearance by the proteasome and autophagy, injure synapses and mitochondria and can seed misfolding in neighbouring cells, so pathology spreads along connections in a prion-like way. The clinical syndrome depends on which circuits are hit, and the same protein can cause different syndromes.
Step by step
- A protein misfolds because of a mutation, ageing or chance.
- Misfolded copies stick together into oligomers and fibrils.
- Chaperones, proteasomes and autophagy fail to clear them.
- Aggregates impair synapses, transport and mitochondria; stress responses fail.
- Seeds pass to connected neurons and recruit normal protein (prion-like spread).
- Vulnerable neuron groups die and glia react; the syndrome follows the circuit.
Proteins and the diseases they define
| Protein | Where it collects | Diseases | Inclusion seen |
|---|---|---|---|
| Amyloid-beta | Extracellular plaques, vessel walls | Alzheimer disease, cerebral amyloid angiopathy | Neuritic plaques |
| Tau | Neurons and glia | Alzheimer disease, Pick disease, PSP, CBD, CTE | Neurofibrillary tangles, Pick bodies, tufted astrocytes |
| Alpha-synuclein | Neurons (Lewy bodies) or oligodendrocytes | Parkinson disease, dementia with Lewy bodies, multiple system atrophy | Lewy bodies, glial cytoplasmic inclusions |
| TDP-43 | Neurons and glia | ALS, frontotemporal lobar degeneration | Ubiquitinated inclusions |
| Polyglutamine (huntingtin, ataxins) | Neuronal nuclei | Huntington disease, spinocerebellar ataxias, Kennedy disease | Intranuclear inclusions |
| Prion protein | Neuropil | Creutzfeldt-Jakob disease and other prion diseases | Spongiform change, PrP plaques |
Clinical notes
- Dementia, movement disorders and motor neuron disease are the main clinical faces; many patients have mixed pathology.
- Biomarkers in CSF, blood and imaging now detect amyloid, tau and alpha-synuclein seeds during life.
Test yourself
Think of the answer, then tap the question to see it.
Which protein forms Lewy bodies?
Alpha-synuclein.
Which protein aggregates in most cases of ALS?
TDP-43.
What does prion-like spread mean in neurodegeneration?
Misfolded protein seeds pass between connected neurons and template the misfolding of normal protein, so pathology advances along circuits.
Elsewhere in DurgiPedia
Connections
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Alzheimer Disease (StatPearls (NCBI Bookshelf), 2026); Prion disease: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026).
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Representative model, for educational purposes only.