neurodegenerative diseases Flashcards
(29 cards)
what is a neurodegenerative disease
the loss of neurons affect CNS/PNS or both begin at any stage of life earlier onset = greater genetic contribution highly heterogenous
features of neurodegenerative disease
molecular impairment somewhere in cell
decreased transmission at synapse
cell death
define Achilles heel
distance between axon terminal and nucleus
describe alzheimers
most common and common cause of dementia
onset usually >65 years
10% nearly onset
not normal part of ageing
shrinkage in brain/hippocampus
proteinopathies = amyloid plaques and neurofibrically tangles
define dementia
decline in memory and other cognitive functions that impair quality of life
what are amyloid plaques
extracellular protein aggregates
enriched in AB peptides
what are neurofibrillary tangles
called paired helical filaments
intracellular protein aggregates
enriched in Tau proteins
what are common causes of Alzheimers
AB = peptide cleaved from transmembrane protein called amyloid beta precursor protein (APP) by proteases
what is the amyloid hypothesis
mutations to 3 proteins involved in AB peptide processing which cause rare early onset alzheimers
tau and neurofibrillary tangles
tau normally binds microtubules in axons
hyperphosphorylated tau is displaced causing: tangles and destabilised microtubules
describe importance of microtubules in neurites
- structure of cell
- positioning of organelles
- motorways for transporting vesicular cargo
describe tau hypothesis
in late onset alzheimers, neurofibrillary tangles are:
- seen before amyloid plaques
- well correlated with cell death and progression
- suggests tau is upstream AB
risk factors for ND
Down syndrome gender (more common in women) high BP, cardiovascular disease low education head injury smoking and drinking
Parkinsons disease
2nd most common
symptoms:
- resting tremor
- bradykinesa
- rigidity
- postural instability
non-motor symptoms of Parkinson’s
depression or anxiety loss of smell sleep disorders constipation dementia other psychotic complications
pathological hallmarks
loss of dopaminergic neurons of substantial nigra and others = dark substance
what is proteinopathy
Lewy bodies
= intracellular protein aggregates enriched in alpha-synnuclein protein
alpha synnuclein = involved in neurotransmitter release
Lewy bodies not pathogenic but increased alpha synuclein is
causes of parkinson’s
10% genetic cause
mutations = later onset
recessive mitochondrial conditions = early/juvenille
early onset mitochondrial PD
damaged mitochondria selectively removed from cell by mitrophagy = auto-Phagy of mitochondrial
loss of function in 2 proteins central to activating mitopahgy = PINK1 and Parkin
describe late onset PD
mutation is a-synuclein gene amplification
LRRK2 gain of function
VPS35 gain of function
GBA loss of function
describe GBA and a-synuclein
GBA encodes Case, a lysosomal enzyme
a-synuclein is degraded in the lysosome
both are connected
increased a-synuclein = decreased GCase = decreased lysosomal function
PD and lysosomes
autophagy is dysregulated in PD brains
problems in autophagy leads to mitochondrial dysfunction
describe risks of PD
risk genes = 30% risk contribute to PD
tau and PD
can be found in PD brains, but not many more NFTs in brains of LRRK2 pD microtubule disruption long implicated in PD Gender = more common in men red hair = x2 risk heady injury not smoking = not consuming caffeine herbicides, pesticides and insecticides exposure to metals general anaesthesia
