5/27- Degenerative Disorders Flashcards
(48 cards)
Symptoms seen with loss of cortical neurons?
Dementia
Symptoms seen with loss of basal ganglia neurons?
Movement disorder
Symptoms seen with loss of cerebellar neurons?
Ataxia
Symptoms seen with loss of motor neurons?
Weakness
What causes neuronal death in degeneration?
Diverse insults
Common final pathways (work in concert):
- Excitotoxicity
- Free radical injury
- Protein fibrillogenesis (extra/intracellular)
(Death via either necrosis or apoptosis)
Consequences of neuronal death (broad, 2)
- System dysfunction
- NT loss
What does it mean if cellular reaction to injury is “reactive”?
It can recover (Necrosis-Apoptosis-Reactive-Normal)
What is protein fibrillogenesis?
Protein misfolds and starts to polymerize/accumulate, aggregating into fibrils or filaments which may lead to cellular dysfunction or death
(early phases e.g. fibrils rather than inclusions are more destructive)
Types of protein fibrillogenesis?
May be:
- Extracellular protein deposit, “plaque”
- Intracellular protein deposit, “inclusion” (most intra are cytoplasmic, but some nuclear) (Innocent bystander proteins may be incorporated into fibrillization/inclusions)
How can fibrillogenesis be identified?
- Light or electron microscopy
- Immunohistochemistry for inclusions in nucleus/cytoplasm
What is the “stress protein”? What does it do?
Ubiquitin
Marks the misfolded protein for refolding or degradation by proteasome
What is a non-proteasome pathway for degradation of misfolded protein?
Autophagy by lysosomes
Composition of cytoplasmic inclusions?
Structural protein:
- Tau
- Synuclein
Stress protein:
- Ubiquitin
- Crystalline
- HSPs
Difference between structure and toxicity of fibrils vs. inclusions?
Fibrils: ultrastructural, nm, VERY toxic
Inclusions: light microscopy, um, less toxic
What is Tau protein? Causes what diseases?
Intracellular neuronal protein associated with microtubules
Causes “Tauopathies”
What is alpha-synuclein? Causes what diseases?
Intracellular neuronal and glial protein
Causes Lewy body disorders, e.g. Parkinson’s
What is superoxide dismutase (SOD)? Causes what diseases?
Intracellular neuronal protein
Causes Familial ALS (can oxidize just fine, but protein misfolds and causes problems)
What is beta-amyloid? Causes what diseases?
Extracellular polymeration
Causes Alzheimer’s Disease
T/F: Neuodegeneration is focal/localized? 3 examples?
False
Neurodegeneration may start focally and then spread
- Alzheimer’s typ starts in hippocampus with memory problems (but may start in Broca’s area with progressive aphasia)
- Parkinson’s may start in 1 substantia nigra; hemikparkinsonism
- ALS may start focally (e.g. hand weakness on 1 side); as dz progresses, it spreads to other muscle groups
Three main steps in prion-like templating of neurodegeneration?
- Misfolding (stochastic, failure to degrade, or genetic propensity to misfold)
- Templating (misfolded pr modifies 2’ structure of native protein in self-replicating cycle)
- Aggregation (misfolded prot tends to aggregate; IC = tangles)
Examples of overlapping neurodegenerative diseases (2)
- Parkinson’s: dementia following movement disorder
- ALS: later frontotemporal dementia
What is a prion?
Misfolded protein that is so capable of modifying 2’ structure of native protein in self-replicating cycle that it is INFECTIOUS
What is this?
Cortical atrophy (caudate atrophy)
Can see hydrocephalus ex vacuo
What is this?
Cortical atrophy: atrophic frontal/temporal lobes moreso than parietal/occipital
