ND Flashcards
What are neurodegenerative disease commonly associated with?
→ ageing
What does earlier or later age of onset indicate about the genetic contribution?
→ greater genetic contribution
→ Later age of onset = more likely a sporadic (or idiopathic)
Are neurodegenerative diseases heterogenous or homogenous?
→ heterogeneous?
Define pleiotropic
→ producing more than one effect
What is the general pattern of neurodegenerative diseases?
→ Molecular impairment somewhere in the cell
→ Decreased transmission at synapse
→ “Dying back” of neurites (axons and/or dendrites)
→ Cell death
What is the distance between axon terminal and nucleus considered as?
→ Achilles heel
What are the common features of NDs?
→ Protein aggregation (“proteinopathies”)
→ Lysosomal dysfunction
→ Mitochondrial dysfunction
→ Associated inflammation via activation of glia
What is the most common cause of dementia?
→ Alzheimer’s
What is dementia?
→ A decline in memory and other cognitive functions that impair quality of life
What is the major hallmark of Alzheimers?
→ brain shrinkage
→ dramatic shrinkage in cortex and hippocampus
What are the proteinopathies of Alzheimers?
→ amyloid plaques
→ neurofibrillary
What are amyloid plaques?
→ Extracellular protein aggregates
→ Enriched in Aβ peptides
What are neurofibrillary tangles?
→ paired helical filaments
→ Intracellular protein aggregates
→ Enriched in Tau protein
What is Abeta peptide cleaved from?
→ transmembrane protein called amyloid beta precursor protein (APP) by proteases
What are the three proteins that can be mutated and involved in Abeta peptide processing?
→ APP
→ PSEN1
→ PSEN2
What are presenillin-1 and Presenillin-2 both a component of?
→ γ-secretase
What does tau normally bind to?
→ microtubules in axons
What does hyperphosphorylation of tau lead to and how?
→ displaced causing:
→ Tangles
→ Destabilised → microtubules
What are the three main roles of microtubules in post-mitotic cells?
→Structure/shape of cell
→ Positioning of organelles
→ Motorways for transporting vesicular cargo
Describe the tau hypothesis
→ typical late onset AD (i.e. not genetic forms of AD
→ neurofibrillary tangles are seen before amyloid plaques
→ Well correlated with cell death and progression
→ Tau is upstream Aβ
What are other risk factors for Alzheimers?
→ Down syndrome (APP is on chromosome 21) → Gender (more common in women) High BP, → Cardiovascular disease, Diabetes → Low education → Head injury → Smoking and drinking
Which gene is most significant for contribution of late-onset AD?
→ APOE gene
What is the second most common neurodegenerative disease?
→ Parkinson’s
What are the motor symptoms of PD?
→ Resting tremor
→ Bradykinesia
→ Rigidity
→Postural instability
What are the non-motor symptoms of PD?
→ Depression & → Anxiety → Loss of smell → Sleep disorders → Constipation → Dementia
What are the pathological hallmarks of PD?
→ Loss of dopaminergic neurons of the substantia nigra and other brain regions
→ Proteinopathy
What are the staining features of PD brain of the substantia nigra?
→ Lack of pigmentation shows loss of substantia nigra
What are the proteinopathies of PD?
→ Lewy bodies
What are Lewy bodies?
→ Intracellular protein aggregates
→ Enriched in α-synuclein protein
What is the normal role of a-synuclein?
→ involved in neurotransmitter release
What does Lewy bodies do to a-synuclein protein?
→ increases a-synuclein
What is the percentage of cases of PD with a clear genetic cause?
→ 10%
What are the three categories familial PD?
→ Early/Juvenile-onset recessive mitochondrial conditions
→ Late/later-onset (usually) autosomal dominant PD
→ Mutations that cause “PD-plus” conditions- very rare
What are some genetic causes found to be linked to PD?
→ SNCA (α-synuclein) gene amplification- Confirms that α-synuclein is pathogenic
→ LRRK2 gain-of-function
→ VPS35 gain-of-function
→ GBA loss-of-function- autosomal dominant, if homozygous then Gacher’s disease
What is GBA?
→ GBA encodes GCase (β-glucocerebrosidase ),a lysosomal enzyme
How is a-synuclein degraded?
→ degraded in the lysosome
What happens with reduced GCase in PD?
→ increased a-synuclein
→ lysosome is impaired
→ autophagy reduced
Where is GCase transported from to the lysosome?
→ Golgi/ER
Explain the pathogenic feed-forward loop of GBA and a-synuclein
→ increased a-synuclein → reduced GCase → reduced lysosomal function
What is consistently dysregulated in PD brains?
→ autophagy
→ lead to mitochondrial dysfunction
What gene encodes tau?
→ MAPT
What are other risk factors of PD?
→ Gender (more common in men) → Red hair (~2x risk) → Head injury → Not smoking, not consuming caffeine → Herbicides, pesticides, insecticides → Exposure to metals (i.e. welder) → General anaesthesia
What is neuroinflammation?
→ activation of the immune system within the nervous system
Which cells are most implicated in neuroinflammation?
→ activated microglia
Why are microglia implicated in neuroinflammation?
→ Amoeboid shape
→ More motile
→ Production of cytokines
What are the microglial activators?
→ α-synuclein
What are the neurotoxic factors?
→ IL-1B,
→ TNF-α,
→ prostaglandins
How can microglia be protective?→
→ anti-inflammatory, e.g. TGFβ
→ normal removal of unhealthy cells (i.e. homeostasis)
How can microglia be damaging?
→ pro-inflammatory, e.g. IL-1, TNF-α
→ response to pathogens etc(i.e. damage to neurons = ‘collateral damage’)
How is the gut linked to PD?
→ Lewy body pathology in gut often precedes pathology in brain
→ Evidence that gut inflammation is sufficient to cause gut Lewy bodies
What are other effects of ageing?
→ Shortening of telomeres in adult stem cells
→ Increased reactive oxygen species
What are some gene expression changes as a result of ageing?
→ Altered Wnt signalling is a big focus in AD and PD
→ Wnts are neuroprotective and neuromodulatory
→ Wnt/β-catenin is decreased in adult brain
→ Deregulated Wnts in developmental and geriatric neuro conditions
