7- Neurodegenerative Diseases

Question 1

what is neurodegeneration?

Answer 1

progressive loss of neurons

Question 2

what are proteinopathies?

Answer 2

umbrella term for neurodegenerative diseases characterised by the accumulation of specific proteins within neurons

Question 3

what are the basic concepts of neurodegenerative diseases?

Answer 3

affect neurons of CNS and/or PNS

highly heterogenous - vary in presentation and root cause
- some disease names are umbrella terms for diseases with overlapping phenotypes but distinct genetic causes
- some diseases have different phenotypic expressions for different individuals

begin at any stage of life
- commonly associated with ageing, later onset = sporadic or idiopathic disease
- earlier age of onset = likely a monogenic disease

Question 4

describe the general pattern/ features of neurodegenerative diseases in affecting neurons

Answer 4

molecular impairment somewhere in neurone cell - tends to affect synapses first

decreased synaptic transmission - more at axon terminals than dendrites - causes electrophysical impairments

leads to ‘dying back’ of neurites - progresses throughout body

leads to neurone cell death which involves
- protein aggregations = contributes to proteinopathies
- mitochondrial and lysosomal dysfunction
- associated neural inflammation from glia activation

Question 5

what is Alzheimer’s disease?

Answer 5

most common neurogenerative disease, common cause for dementia

ate of onset usually above 65yrs BUT isn’t a normal part of ageing

Question 6

what is dementia? presentation:

Answer 6

a decline in memory and other cognitive functions that impair quality of life

presentation:
- memory loss of things they shouldn’t be forgetting
- abnormal changes in behaviour, cognition and psychology

more sudden, irrational and unreasonable change in personality, behaviour and cognition compared to normal ageing

Question 7

pathological hallmarks of dementia?

Answer 7

brain shrinkage - hippocampus and cerebral cortex shrink, enlargement of ventricles

two types of proteinopathies
- amyloid plaques
- neurofibrillary tangles

Question 8

what are amyloid plaques? how does the amyloid hypothesis contribute to Alzheimer’s?

Answer 8

amyloid plaques are aggregates of A-beta protein

forming A-beta & amyloid plaques:
- APP transmembrane protein is cleaved by beta-secretase, then gamma-secretase = produces and releases A-beta
- A-beta proteins aggregate and form extracellular amyloid plaques

(monogenic) mutations to 3 potential proteins contribute to earlier-onset Alzheimer’s induced by amyloid plaques:
mutations to APP protein, or PSEN 1 or 2 (components of gamma-secretase)

production of amyloid plaques contributed to neurone cell death and Alzheimer progression

Question 9

what are neurofibrillary tangles? how does the Tau hypothesis contribute to Alzheimer’s?

Answer 9

neurofibrillary tangles formation
- Tau proteins is normally found intracellularly bound to axon microtubules
- Tau can be phosphorylated = detaches form microtubules and aggregates to form neurofibrillary tangles
- destabilises microtubules = affects their function of maintaining cell shape and structure, correctly positioning organelles and vesicular transport

Tau hypothesis:
-Tau protein aggregates destabilise microtubules - affect cell structure/ shape/ function/ organelles = leads to neuronal cell death
- Tau aggregates are seen before amyloid plaques and correlate with pathological neuronal cell death & disease progression

Question 10

debate the Tau and amyloid hypothesis

Answer 10

Tau aggregates are seen before amyloid plaques and correlate with pathological neuronal cell death & disease progression
- neurofibrillary tangles destabilise microtubules and affect cell structure/ shape/ function/ vesicular transport and organelle positioning = leads to neuronal cell dysfunction and death

suggests Tau aggregates are upstream of amyloid plaques

however - amyloid plaques and Tau tangles could be downstream events for something else, or a protective function, or just a by-product of neurodegeneration

Question 11

risk factors for Alzheimer’s

Answer 11

age

mutations in APP protein, or PSEN 1/2 = small genetic risk

Down’s syndrome - APP gene is on chromosome 21, Down’s is trisomy 21

gender - more common in women

high blood pressure, CV disease, diabetes

low education - better education, can deal with NDs better

head injury

smoking and drinking

Question 12

what is Parkinson’s disease?

Answer 12

the second most common neurodegenerative disease - onset is usually between 60-65yrs

movement disorder

Question 13

what are the 4 main motor symptoms of Parkinson’s?

Answer 13

slow movement/ bradykinesias

postural stiffness = risk for fracturing bones, affects life quality and expectancy

resting tremor = present when person’s hands are still, progresses from one side to the other

rigidity = causes slow, shuffling gait and hunched shoulders

resting tremor is the earliest symptom - as that progresses the others also emerge with slow movement, rigidity and postural stiffness

Question 14

what are the non-motor symptoms of Parkinson’s?

Answer 14

depression and anxiety
loss of smell
sleep disorders
constipation

rarer - dementia, other psychiatric complications

non-motor symptoms can occur before motor dysfunction

Question 15

list all the symptoms (motor and non-motor) for Parkinson’s

Answer 15

rigidity
postural stiffness
slow movement
resting tremor

depression and anxiety
dementia/ psychiatric complications
loss of smell
sleep disorders
constipation

Question 16

what are the pathological hallmarks for Parkinson’s?

Answer 16

loss of dopaminergic neurons from substantia nigra
- normally dopaminergic neurons are visible as dark stripes on the sides of brain as they express neuromelanin
- loss of pigmentation/ dark stripes in Parkinson’s is visible

Lewy bodies as a-synuclein protein aggregates

Question 17

what is the significance of a-synuclein and its aggregates in Parkinson’s?

Answer 17

a-synuclein is an intracellular protein - regulates synaptic vesicle trafficking and neurotransmitter release

aggregates of a-synuclein = Lewy bodies - pathogenic in the sense that there’s an increase in a-synuclein

Question 18

what are the three different categories/causes for genetic Parkinson’s?

Answer 18

early/juvenile onset Parkinson’s by recessive mitochondrial conditions

late onset autosomal dominant Parkinson’s

mutations that cause ‘Parkinson’s-plus’ conditions

Question 19

describe early onset mitochondrial Parkinson’s - when it occurs? causative mutation?

Answer 19

manifests before 50yrs

cause:
- damaged mitochondria are selectively removed from cell by mitophagy
- specific loss-of-function mutations in PINK1 and Parkin proteins that are essential for mitophagy are associated with early-onset Parkinson’s

Question 20

what is late onset genetic Parkinson’s?

Answer 20

occurs after 50 yrs, associated with a combination of environmental and genetic factors

less of a strong genetic component

Question 21

describe the potential genetic causes of late onset Parkinson’s and how they contribute to the disease

Answer 21

genetic causes/ mutations:
SNCA1 gene amplification - encodes a-synuclein
GBA gene loss of function - encodes lysosomal enzyme GCase

mechanism:
normally functional GBA gene expresses GCase - lysosomal enzyme that digests a-synuclein via autophagy = a-synuclein is broken down

with loss-of-function GBA mutation = loss of GCase = reduced lysosomal function = increase in a-synuclein = greater loss of GCase - creates a positive feedforward loop
- impaired lysosomal function from loss of GCase allows a-synuclein to accumulate and form Lewy bodies = accumulation of a-synuclein is what’s pathological

Question 22

what is autophagy? why is it important and how does it contribute to Parkinsons?

Answer 22

autophagy - process that degrades and recycles cellular components = removes damaged/ toxic components, prevents their accumulation

many Parkinson’s disease mutations involve lysosomal dysfunction = impair autophagy = impair mitophagy = allows mitochondrial dysfunction to build-up and accumulate = affects neuronal cell function and causes it to die