Flashcards in PD: Mechanisms of Neurodegeneration Deck (23)
Why do DA neurons degenerate?
- oxidative stress
- mitochondrial dysfunction
- ubiquitin-proteasome dysfunction
Describe ubiquitin-proteasome pathway
Polyubiquitin chain conjugated to substrate to tag it for degradation by
PD causing mutation -> disrupted ubiquitination -> decreased degradation of damaged proteins -> protein aggregate -> cell death
Genetic causes of defects in ubiquitin-proteasome pathway?
PARKIN gene (associated w/ E3 ligase)
NB: E1, E2, E3 are enzymes involved in ubiquitination
Mechanism of ROS generation in PD?
DA and its metabolites have tendency to form ROS
SNpc is rich in iron, redox cycles of iron generate ROS
Mitochondrial dysfunctions uncouple redox reactions -> ROS
Genetic causes of ROS generation in PD?
Deficiency in antioxidant molecules (glutathione) -> ROS generation
Mechanisms of mitochondrial dysfunction in PD?
a-synuclein aggregates can inhibit complex 1->mitchond. dysfunction
ROS -> dysfunction
DJ1 mut-> Mitochondrial membrane dysfunction -> dysfunction
Mitochondrial dysfunction -> Cyt C released -> apoptosis
Mechanism of neuroinflammation in PD?
[6-OHDA, MPTP] -> direct microglial activation and indirect (LPS) neurotoxins
Overview of midbrain DA neurons?
nigrostriatal: DA neurons in SNpc innervate the dorsal striatum
mesocorticolimbic: VTA neurons innervate nucleus accumbens and olfactory tubercle (via mesolimbic and mesocortical projections)
Overview of theories of SNpc DA neurons susceptibility?
- environmental toxins lead to specific degeneration of SNpc neurons
- transcriptional profile may confer inherent invulnerability of SNpc DA neurons
- VTA neurons are more resilient than SNpc neurons
How can environmental toxins lead to specific degeneration of SNpc neurons?
MPTP-induced Parkinsonism discovered in heroin users]- MPTP inhibits complex 1
uptake of MPP+ is specific for SNpc neurons, concentrated in mitochondria
NB: not true PD as you are artificially killing DA neurons to produce a similar state
Neurodevelopment of DA neurons?
Neural stem progenitor cell -> mDA progenitor -> mDA immature neuron -> mDA mature neuron
Main features of DA neuronal transcriptional profile
- Defined as midbrain neurons
- Define by DA neurons
- [in adult]: survival/maintenance factors
Overview of genetic influence of transcriptional profile of DA neurons?
Regional identity: Otx2 (SHH, Wnt1, engrailed)
Specification: LMX1a (FGFB, SHH)
Survival: Engrailed, Nurr 1
Nurr 1 role (and experimental evidence)?
Regulates NT indentity of neuron
Nurr-1 deficiency -> DA neurons can't produce DA
FoxA2 role (and experimental evidence)?
Involved in late-stage DA neuron develeopment
Heterozygotes FoxA2 (+/-) mice -> unilateral DA neuron degeneration
Engrailed experimental evidence?
Engrailed KO -> total loss of DA neurons (dose-dependent)
Heterozygote -> cell lost by P90
Compare resilience of VTA and SNpc neurons (and experimental evidence)?
Otx2 upregulated in VTA > SNpc
Otx2 overexpression in SNpc -> neuroprotective
Overexpression of pro-survival genes (upreg in VTA but downreg in SNpc) -> neuroprotective
Overview of genes involved in PD?
- SNCA (codes for alpha-synuclein)]- first PD gene found
- Parkin]- most common genetic cause; autosomal recessive PD
SNCA: wild type vs mutated (+experiment)?
WT: pre-synaptic vesicle trafficking?
mut: proteasome inhibition, complex-1 inhibition, autophagy inhibition, form LBs
SNCA KO mice -> resistnance to MPTP-induced DA activity
Parkin: wild type vs mutated (+experiment)?
WT: E3 ligase adds ubiquitin and aids degradation
mut: Parkin KO -> unable to remove/break down damaged proteins + organelles
PINK-1: wild type vs mutated (+experiment)?
WT: marks mitochondria (removed by Parkin)
Parkin overexpression -> rescues PINK1 KO
DJ1: wild type vs mutated (+experiment)?
WT: inhibits aggregation of alpha-syn (via its chaperone activity), antioxidant, modulate mitoch. membrane potential
DJ1 KO -> disrupted mit. membrane potential -> marked by PINK-1 to be removed by Parkin for degradation