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PH-NE15

Other neurodegenerative diseases

How misfolded tau, TDP-43, alpha-synuclein, huntingtin and prion protein spread through particular networks, causing frontotemporal dementia, Lewy body dementia, PSP, MSA, Huntington disease, motor neurone disease and CJD.

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  • 6 steps · 10 questions
  • 3D normal anatomy

By the end, you can

  • Explain how neurones normally keep proteins folded, and how misfolded proteins aggregate, template normal copies and spread along connections.
  • Relate the protein and the network first affected to the features of frontotemporal dementia, dementia with Lewy bodies, progressive supranuclear palsy and multiple system atrophy.
  • Explain how an expanded CAG repeat in Huntington disease leads to striatal loss and chorea, and how loss of upper and lower motor neurones produces the mixed signs of motor neurone disease.
  • Describe how prion protein misfolds and why prion diseases are transmissible and rapidly progressive.
  • Recognise the classic appearances, criteria and tests of these diseases, and explain how the main treatments act on the failing networks.

What it is

Neurodegenerative diseases are progressive losses of particular groups of neurones, usually marked by aggregates of one misfolded protein. Besides Alzheimer’s and Parkinson’s disease, they include frontotemporal dementia (tau or TDP-43), dementia with Lewy bodies and multiple system atrophy (alpha-synuclein), progressive supranuclear palsy (tau), Huntington disease (huntingtin with an expanded polyglutamine tract), motor neurone disease (mostly TDP-43) and the prion diseases (misfolded prion protein), which alone are transmissible.

5 types to tell apart
Tauopathies
Tau aggregates: frontotemporal lobar degeneration with tau (including Pick disease), progressive supranuclear palsy and corticobasal degeneration; Alzheimer’s disease has tau with amyloid.
Synucleinopathies
Alpha-synuclein aggregates: Parkinson’s disease and dementia with Lewy bodies (in neurones) and multiple system atrophy (in oligodendrocytes).
TDP-43 proteinopathies
TDP-43 leaves the nucleus and aggregates in the cytoplasm: most motor neurone disease and about half of frontotemporal dementia.
Polyglutamine (repeat) diseases
An expanded CAG repeat adds a long glutamine tract to a protein: Huntington disease and some inherited ataxias.
Prion diseases
Misfolded prion protein templates normal copies and is transmissible: sporadic, familial and acquired Creutzfeldt–Jakob disease and rarer forms.

US spelling: behaviour → behavior.

Normal function

Neurones that must keep their proteins in shape for life

A neurone lives as long as its owner and never divides. Proteins made in the must travel along the to the , sometimes a metre away. Several proteins central to this lesson do everyday jobs there: tau binds and stabilises the microtubules of the axon; TDP-43 works in the , processing RNA; alpha-synuclein sits at the terminals, helping release transmitter; huntingtin helps transport and gene control; and prion protein sits on the cell surface.

Proteins are kept folded by chaperones. A single misfolded protein is tagged with ubiquitin and destroyed by the proteasome; larger clumps and worn-out mitochondria are removed by autophagy and lysosomes. A dividing cell can dilute its damaged proteins; a neurone cannot, and these clearance systems decline with age.

Different groups of neurones serve different networks: the frontal and front temporal lobes for behaviour and word meaning, the striatum for selecting movements, the midbrain for vertical gaze, the cerebellum and autonomic neurones for coordination and blood pressure, and upper and lower motor neurones for voluntary movement. Each disease begins in one network, which is why the symptoms differ even when the mechanism is shared.

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