Parkinson's Pathogenesis Flashcards
What sex is more likely to get PD?
Male
What are the 3 types of PD onset?
Juvenile - before 20
early - 20-50
Late - after 50
What are 2 environmental risk factors?
Head trauma
Pesticide/herbicide exposure
What % of PD patients have a family history?
15 (5-10% have monogenic forms)
What 2 environmental factors can be protective in a dose-dependent manner?
caffeine
smoking
What are autosomal dominant PD?
Autosomal dominant mutations in SNCA (PARK1) & LRRK2 (PARK8)
What are autosomal recessive PD?
mutations in PRKN (PARK2), DJ-1 (PARK7) and PINK1 (PARK6)
What are genes resulting in mendelian forms of parkinsonism?
PARK genes
What does SNCA encode?
alpha-Syn that codes for protein alpha-synuclein
mutation on exon 4
What does SNCA have similiar clinical & pathological marks to?
idiopathic PD
What is SNARE complex responsible for?
fusion of NTs to synaptic membrane
Where is LRRK2 mutated?
G2019S mutation
Which patients is the LRRK2 mutation found in?
Later age onset
Idiopathic PD
What 4 functions is LRRK2 involved in?
Cell signaling
autophagy
Trafficking
mitochondrial function
What 3 things does increased LRRK2 kinase activity cause?
Impaired vesicle trafficking & lysosome function
Promotes neuroinflammation
What do LRRK2 alleles affect?
Neuroinflammation
What do WT LRRK2 variants play a role in?
Idiopathic PD
Where is the PRKN gene mutation found?
Chromosome 6
What 2 characteristics do PRKN mutations have?
Typical PD features
lower-limb dystonia
What 3 types of PD is PRKN gene mutation most common in?
Early-onset autosomal recessive PD
Sporadic early/late-onset
What 3 things is PRKN involved in?
Autophagy
Apoptosis
mitochondrial clearance
What 3 types of mutations are PINK1 mutations?
Point
frameshift
truncating
What type of PD does PINK1 mutations cause?
early onset recessive PD
What 4 mutations are DJ-1 mutations?
Missesne
whole exon deletions
frameshift
splice site
What type of PD is DJ-1 mutations found in?
Early onset
What are PINK1 and DJ-1 involved in?
Maintenance of mitochondrial homeostasis
What is MAPT?
protein hat encodes tau
What are 2 major haplogroups of MAPT?
H1 and H2 due to chromosome inversion
What do mutations in cases with MAPT & SNCA cause?
Parkinsonism with dementia
What PD cases does MAPT have a role in?
Familial cases
Sporadic PD
What 4 genes is molecular diagnostic testing used for?
PRKN
PINK1
DJ-1
LRRK2
What PD is molecular diagnostic testing used for?
Early onset - test for PRKN
Is molecular diagnostic testing used for onset above 40?
No as PRKN mutation is quite low & its expensive
What screening is done for late onset idiopathic PD?
3 most common mutations in LRRK2
familial history
What are the 3 mutations screened for LRRK2
codons 1441, 2019, 2020
What are 4 synucleinopathies?
PD
PD dementia
Dementia with lewy bodies
Multiple system atrophy
What are 4 steps of alpha syn & tau in NDG?
- alpha syn inhibits tubulin binding to tau
- alpha syn promotes tau phosphorylation
- alpha syn triggers tau polymerization
- alpha syn spreads & seeds tau inclusion
What happens if mitochondrial is depolarized?
lose different conc. in electron & proton = loss of ATP
What NT is excessively released into substantia nigra pars compacta in pD?
Glutamate -> too high Ca2+ -> disruptive cascades
What 2 structures release cytokines in PD?
Astrocytes
microglia
What are 2 types of immunotherapy?
Antibodies & inhibitors of neurotoxic agents
Conformation-specific antibodies bind alpha-syn
failed in 2022
What immunoglobulin target alphasyn?
Humanized IgG1 monoclonal anti-alphasyn antibodies
