Neurological disorders Flashcards
what is meant by a neurons “achilles heel”
distance between axons terminal and nucleus
what is dementia
a decline in memory and other cognitive functions that impair quality of life
what are the pathological hallmarks of Alzheimer’s
- Brain shrinkage ( shrinkage of cerebral cortex and hippocampus)
- Proteinopathies
Proteinopathies in Alzheimer’s
- amyloid plaque
- -Extracellular protein aggregation
- -enriched in Abeta peptides
- Neurofibrillary tangles
- also called paired helical filaments
- -intracellular protein aggregates
- -enriched Tau protein
Abeta and APP
Abeta peptide is cleaved from a
transmembrane protein called amyloid
beta precursor protein (APP) by proteases
AMYLOID HYPOTHESIS
• Mutations to three proteins involved in Abeta peptide processing
are known to cause rare early onset forms of Alzheimer’s
— APP
— PSENI
— PSEN2
Presenilin-l and PreseniIin-2;
both a components of y-secretase
TAU AND
NEUROFIBRILLARY TANGLES
• Tau normally binds microtubules in axons •Hyperphosphorylated tau is displaced causing: — Tangles — Destabilised microtubules
Other risk factor of Alzheimer’s
- Down syndrome (APP is on chromosome 21 )
- Gender (more common in women)
- High BP, Cardiovascular disease, Diabetes
- Low education
- Head injury
- Smoking and drinking
Symptoms of parkinsons disease
resting tremor, bradykinesia, rigidity,postural instability
Non motor symptoms of Parkinson’s (4 pts)
-depression and anxiety
-loss of smell
-sleep disorders
-constipation
less common( dementia and other psychiatric complication )
Pathological hallmarks of Parkinson’s
- loss of dopaminergic neurons of the substantia nigra
- proteinopathies
proteinopathies of Parkinson’s
Lewy bodies — Intracellular protein aggregates — Enriched in a-synuclein protein Normal role of a-synuclein is poorly understood (involved in neurotransmitter release) • Lewy bodies not pathogenic, but increased a-synuclein is
EARLY ONSET
MITOCHONDRIAL PD
- Mitochondria have a finite lifespan due to oxidative stress
- Damaged mitochondria are selectively removed from the cell by “mitophagy” - autophagy of mitochondria
- Loss-of-function mutations in two proteins central to activating mitophagy — PINKI and Parkin — cause EO PD
LATE ONSET GENETIC PD
Some genetic causes found from kindred studies (like EO
PD), but more limited, including:
-SNCA (a-synuclein) gene amplification
• Confirms that a-synuclein is pathogenic
-LRRK2 gain-of-function
-VPS35 gain-of-function
-GBA loss-of-function
GBA & a-SYNUCLEIN
-GBA encodes GCase (ß-glucocerebrosidase),
a lysosomal enzyme
-a-synuclein is degraded in the lysosome
