PD Causes and Disease Mechanisms Flashcards
What are the clinical symptoms of PD
Pre-Motor symptoms (constipation, loss of smell and depression) and Post Motor Symptoms (Hallucinations, Psychosis, Postural instability)
Motor symptoms - Bradykinesiia, Akinesia
Responsive to L-Dopa therapy
What are the pathological features of PD
Lewy bodies (Perikyra) and Lewy neutrites (processes), these are intraneuronal inclusion bodies which invole asyn aggregates Loss of dopaminergic neurons in the Substania Nigra The neuropathology of PD appears to spread through anatomically connected regions of the brain in accordance to Braak's Model
What is the Incidence of PD
1-5 in 1,000
Onset variable, early (~40s) or late (~65)
What are other diseases with the histopathological features of PD?
MSA
Dementia with Lewy Body Disease
Incidental LBD
Genetic Risk Factors?
The genetic risk factors are relatively uncommon (11 risk loci and 5 extra upon meta analysis)
Monozygotic and Dizygotic studies in twins - low concordance, except between mono with early onset
Environmental Factors
Smoking, Coffee = protective
Industrialisation is associated with a higher incidence in population
P450 detoxification defects (CyP2D6) - 2.4 times higher risk
In Guam a higher incidence, associated with the type of meat they eat there
Environmental factors that are complex I inhibitors e.g. MPTP and rotenone
What does MPTP stand for
N-Methyl-4-phenyl-1,2,3,6-tetrapyrimidine
What is MPTP’s pathogenic mechanism in teh brain
It passes through the blood brain barrier thanks to its highly lipophilic characteristics. Here it is converted by monoamine oxidase B to MPTP+ –> MPP+ via spontaneous oxidation
Describe Oxidative Stress in PD patients
- Increased Iron Levels
- Decreased reduced glutathione
- Decreased copper/zinc superoxide dismutase activity
Describe proteasomal defects in PD patients
UPS
- Decreased proteasomal activity
- LB are ubiquitinated, suggesting an inhibited UPS pathway
- Decreased UPS activity in patients
- Injecting proteasome inhibitors in rats results in SN degeneration
Describe the lysosomal defects in PD patients
- Decreased CMA proteins (LAMP2A and Hsc70)
- Decreased lysosome number lysosomal proteins (LAMP1 and Cathespin D)
- Increased number of autophagosomes, possibly due to decreased clearence by lysosomes
In the Braak (2003) staging of PD where do the aggregates begin - and where do they spread to (name 6 stages)
- Dorsal Motor Nucleus
- Lower Rophe nuclei
- Sub. Nigra (Motor Symptoms)
- Temporal mesocortex
- Temporal Neocortex
- Neocortex
- -> this notion suggested the idea of prion-like hypothesis, supported by grafting (li et al. 2008/2010) –> Hansen et al. 2011 –> Angot et al. 2012 –> Reyes et al. 2011/2013 - specifically reyes who showed that injection into olfactory and mapped for 72 hours demonstrated spread through anatomically connected regions, suggesting potential for environmental exposure
Where is asyn phosphorylated?
Serine 129
What are the pre-motor symptoms
Loss of smell
Depression
REM sleep disorder
Constipation (suggestive of environmental toxins orginating in the stomach) (supported by findings of LB in enteric nervous systems
Motor symptoms?
Bradykinesia - slowness of movement
Akinesia - Loss of Movement
Tremor
Post motor symptoms
Dementia (80% after having PD for 20 yrs)
Visual halucinations
Postural instability
Speed problems
What did Tanner et al. 1999 describe
No correlation in twins (di or mono)
Except that for earlier onset PD there was a greater correlation between mono - this is supported by the fact that many AR mutations cause earlier onset, finding since been supported by improved genomic technology
How many PD cases caused by LRRK?
2-40% in familial
1-2% overall
How many PD cases caused by GBA?
9-18% in familal 6-8% overall --> greater correlation with heterozygous GBA mutants --> 31.4% in Ashenkazi jews --> 4% in normal PD population from UK
How many loci by GWAS?
11
How many “risk loci” by meta analysis
5
What is the issue with associating environmental risk with PD?
Tanner et al. 1989 - studies demonstrating regions of higher industrialisation rates were at greater risk. However,
Environmental studies, epidemiology is correlative with areas that are more industrialised where individuals are exposed to chemicals that mimic the structure of MPTP. Hypothesised that environmental factors contribute to the risk of developing Parkinson’s - however, this has yet to be proven as individual molecules and the mechanistic role they play in the pathophysiological development of hallmark PD features has yet to be assessed
Describe the cytochrome p450 system
First enzymatic defence system against toxic compounds. In a typical defence system cytochrome p450 uses an oxygen, NADH and hydroxyl compound to detoxify the agent (typically a pharmaceutical compound) - as a consequence the product of this system is more reactive than the primary - thereby if it is not taken on to the next step (phase II) it can cause more damage unto lipids, proteins and nucleic acids. Induced phase I or reduced Phase II has been implicated in Parkinsons
What is Beta-methylamino-L-alanine
It is a substance found in cyads that accumulated in the flying fox bat in guam that lead to a high incidence of disease that was similar to that of AD, PD and dementia. It was coined Lytico-Bodig.
If the villagers were westernised the disease would go away.
What is the disease mechanism of Beta-methylamino-L-alanine?
Beta-methylamino-L-alanine is thought to induce exocitoxicity in glutamate receptors in neurons, it is thought, activation of the metabotropic glutamate receptor 5 is believed to induce oxidative stress in the neuron by depletion of glutathione (common symptom of PD). Additionally can incorproate itself into proteins, through replacing L-serine —> misfolding. Green Monkey subjects were feed BMAA with serine demonstrated 70% less beta-amyloid deposition, suggestive that serine acts as a neuroprotectant (Cox et al. 2015) - also first in vivo model of both beta amyloid and hyperphosphorylated tau
What does MPP+ stand for
1-methyl-4-phenyl-pyridinium cation (spantaneous oxidation) enters neurones through uptake by dopaminergic transports
–> SN are already susceptibile to OS thanks to the production of dopamine
What are Rho 0 cells?
Cells with no mtDNA due to incubation with ethidium bromide
What is the percent of mtDNA deleted in age-related controls?
> 60%, cytochrome oxidase deficient cells
- -> in PD not much greater
- -> is PD therefore an accelerated ageing phenotype?
What does MDA stand for
Malondialdehyde
What does MDA do?
It is a lipid peroxidation product and acts as a signalling molecules
Very recent research indicated that MDA acted as a signaling messenger and regulated islet glucose-stimulated insulin secretion (GSIS) mainly through Wnt pathway. The moderately high MDA levels (5 and 10 μM) promoted islet GSIS, elevated ATP/ADP ratio and cytosolic Ca2+ level, and affected the gene expression and protein/activity production of the key regulators of GSIS (Xang et al. 2014)
What is an additional production of lipid peroxidation?
4-hydroxynonenal (4-HNE), which is highly toxic and can lead to more stress
What is the significance of LRRK2 in serine129 phosphorylation
It is thought that LRRK2 can phsophorylate serine through its kinase abilitiy - with mutations causing constitutive activation
What is the percentage of serine 129 phosphorylated in normal brains versus PD
4% versus 90%
What is the proposed role of Asyn?
- unknown
- long-term maintenance of vesicle pools
- directly implicated in release of dopamine through association with SNARE complex
- its potentially multi-functional properties that have been proposed could be thanks to its conformational flexibility
What are the apparently neuroprotective effects of asyn
Chandra et al. 2005
Mide studies deficient in cystein string protein a demonstrated asyn to protect against progressive degeneration, suggesting that asyn function is more predominant underconditions of stress
CSPa is a co-chaperone, possibly they work together?
CSPa aids SNARE assembly - this provides us a link between the two
Describe its role in vesicle pools?
Cabin et al. 2002
Chandra et al. 2002
- deficient mice generated through HR in ESCs
- these mice couldnt release synpatic vesicles even following long-term stimulation
- chandra however appears to dispute this notion, however they deleted exon 1+7 as aposed to 4+5
- however they found dopamine levels to be 20% lower, suggesting possible maintenance in pools, suggesting long term maintenance
- isssue could be resolved with Cas/CRSPR
What form does PD exist in the brain?
Monomeric (Fauvet et al. 2012)
What is the issue with in vitro and in vivo work on asyn
still dont know the conformation
What suggests that phosphorylation plays a role in aggregation?
Treatment with caesin kinase inhibitors and phophotases in transgenic mice demonstratedto prevent aggregation
Describe li et al.’s work
Progressive asyn in gradts, in 12 year old graft there was 40% asyn and 1.9% LW
In 16 yo graft there was 80% asyn and 5% LB
(3% LB in PD)
Describe Chu et al. 2007
asyn increases with age, at 65 in a normal individual there will be 4.5 X 10-4
These grafts, following the linear graph Chy et al. created should have had no asyn
Describe Hansen et al.’s 2011
- Fluorescent tags + co-culture, where the tags driving the transmission
- Indirect staining between co-culture of mouse (dont express asyn) and human, using abs specific for human and mouse - confirmed transmisiosn - also confirmed human as donor
- Truncated GFP and non-truncated - demonstrated seeding effect
Describe Angot et al. 2012
Generated a model in hopes of recapitulating the transplantation paradigm by li et al.
- AAV injected “host” + grafted neurons (all in mouse brain)
- high transfer rate, with some discrepencies suggesting a dynamic process of degradation
- Visualisation of the mouse grafted neurons demonstrated an epicentre of human and then total ab stain surrounding, seeding for both mutant and WT
Luk et al. 2012
- -> confirmed spread of asyn in PFF, performed in both transgenic and non-transgenic, demosntrating the potenital for PD to be encouraged by genetic risk factors, or simply environmental exposure
- -> saw pathological spread, despite injections in striatum and cortex
- -> further supported by other primary culture works which demonstrated PFF to recruit endogenous asyn
