L18 - Neurodegenerative Diseases Flashcards
What is a Neurodegenerative disease and what its features?
Any disease caused by the progressive loss of neurons. They can affect CNS or PNS. They can begin at any stage of life.
How are Neurodegenerative diseases heterogenous?
They are very varied in their presentation.
- some diseases are umbrella terms (have overlapping phenotypes but a distinct genetic cause)
- Some diseases are pleiotropic (some symptoms manifest differently in different people)
Describe the common pattern which neurodegenerative disorders follow?
- Molecular impairment somewhere in the cell
- decreased transmission at the synapse
- dying back of neurites (axons or dendrites)
- cell death
State some common features of neurodegenerative disorders?
usually involve:
- protein aggregation
- lysosomal dysfunction
- mitochondrial dysfunction
- associated inflammation via activation of glia
What is Dementia?
A decline in memory and other cognitive functions that impair the quality of life.
Impairments in dementia are distinct from normal cognitive lapses.
The most common cause of dementia is Alzheimers
Describe some pathological Hallmarks of Alzheimers?
- Brain Shrinkage
(smaller brain, deeper sulci) - Proteinopathies
(amyloid plaques and neurofibrillary tangles)
What are Amyloid Plaques?
- extracellular protein aggregates
- enriched in A beta peptides
- A-beta peptide is cleaved from a transmembrane protein called APP
- cleavage occurs via Beta -secretase and Gamma- secretase, and this results in an accumulation of A beta fragmants, causing Amyloid plaques.
-Mutations in APP, PSEN1 and PSEN2 are known to cause rare early onset of Alzheimers (PSEN1 and PSEN2 are both components of gamma - secretase)
What are Neurofibrillary tangles?
- AKA paired helical filaments
- intracellualr protein aggregates
- enriched in Tau protein
- Tau is usually found bound to Microtubules in axons
- When it is Hyperphosphorylated, it is displaced from the microtubules which causes tangles of Tau. By detaching, it also destabilises microtubules - which leads to cell death
Describe the importance of Microtubules in Neurites?
- structure and shape of the cell
- positioning of the organelles
- act as motorways for transporting vesicular cargo
State some risk factors for Alzheimers Disease?
- Down’s syndrome
- Gender (more common in women)
- High BP, CVD, Diabetes
- Low education
- Head Injury
- Smoking and drinking
- small genetic risk
What is Parkinson’s Disease and what are its 4 main features?
It is a neurodegenerative movement disorder.
features:
- resting tremor
- Bradykinesia
- rigidity
- postural instability
What are some non-motor symptoms of Parkinson’s disease?
- depression and anxiety
- loss of smell
- sleep disorders
- constipation
- dementia
- other psychiatric disorders
Describe some pathological hallmarks of Parkinson’s Disease?
- loss of dopaminergic neurons of the substantia nigra
- proteinopathy (lewy bodies rich in a-synuclein)
What are the 3 categories of Familial Parkinson’s Disease?
- early onset of recessive mitochondrial conditions
- late onset of autosomal dominant Parkinson’s Disease
- Mutations that cause PD-plus conditions
Describe early onset mitochondrial Parkinson’s Disease?
- mitochondria have a finite lifespan due to oxidative stress
- damaged mitochondria are selectively removed from the cell by mitophagy
- loss-of-function mutations in 2 proteins central to activating mitophagy - PINK1 and Parkin, cause early onset PD
