Comparing Neurodegenrative Diseases

Question 1

Summarise the brain regions and symptoms seen

Answer 1

AD
= frontal + temporal cortex , hippocampus
= reasoning + language problems
= memory loss

PD
= basal ganglia (substantia nigra)
= bradykinesia + akinesia

Prions
= cerebellum + cortex
= ataxia

HD
= cortex + CPU
= movement problems

MND
= motor cortex, brain stem , spinal cord
= abnormal reflexes
= muscle weakness

Question 2

What are the proteinopathies involved?

Answer 2

AD
= β-amyloid (extracellular)
= Tau (intracellular)

PD
= α-synuclein (intracellular)

Prions
= PrPSc (extracellular)

Huntington’s
= Huntintigtin (intracellular)

MND
= TDF-43 (intracellular)

Question 3

What are some common themes in other factors?

Answer 3

Environmental
= e.g. BMAA
= ALS-PD-dementia complex

Glutamate excitiotoxicity
= BMAA is a glutamate agonist
= memantine, riluzole = treatments for AD and MND

Damage to mitochondria and oxidative damage
= PD from both genetics and environment
= seems to apply to all neurodegenerative disease

Defects in ubiquitin protease system
= good evididence in PD
= all proteinaceous inclusions are ubiquitinated

Inflammation
= recent discovery of TREM2 (anti-inflammatory protein) as a risk factor for AD, PD, MND

EXTRA READING - TREM2
= Triggering Receptor Expressed on Myeloid Cells 2
= expressed on microglia
= regulates function of microglia
= modulate microglial phagocytosis, cytokine production and cell survival
= linked to AD, PD and frontotemporal dementia
= may also play role in clearance of Aβ plaques in AD (could be treatment target)
= also plays role in multiple sclerosis, ischemic stroke and traumatic brain injury

Question 4

What are some common themes in the prion-like spread of pathology?

Answer 4

Protein aggregation often begins in specific regions of brain
= then spreads to other areas

Research on prion-like mechanism
= involving seeding and propagation of protein misfolding and aggregation

Protein aggregation can be ‘seeded’ experimentally even in diseases that are not overtly infectious
= e.g. AD and PD

= good evidence in case of: Aβ, tau, α-synuclein , TDP-43

Question 5

EXTRA READING - Frontal Temporal Dementia (FTD)?

Answer 5

= group of disorders characterised by degeneration of frontal / temporal lobes of brain

= changes in personality, behaviour and language

= can also lead to motor symptoms - e.g. parkinsonism

= can be sporadic or familial

= includes mutations in:
MAPT = makes tau protein = abnormal accumulation = also AD

GRN (progranulin) = progranulin protein involved in inflammation, wound healing, neuronal survival

C9orf72 = also MND = contains repeat expansion of noncoding sequence = abnormal RNA and protein accumulation

(also TBK1 and CHMP2B)

= includes proteinopathies in:
Tau = also AD

TDP-43 = also MND

FUS = also MND