modelling molecular mechanisms of Parkinson's Disease in human stem cells and transgenic animals Flashcards
What is the function of dopamine neurotransmitter, what disease is associated with this and what is the treatment used for this disorder as well as the outcomes?
Dopamine neurotransmitter that plays a crucial role in controlling movement, among other functions. In Parkinson’s disease, the neurons in the brain that produce dopamine are damaged and die, leading to decreased dopamine levels and, consequently, the motor symptoms of the disease. This means that once L-DOPA is administered and crosses the blood-brain barrier, it can be converted into dopamine in the brain. This conversion helps to increase dopamine levels within the brain and improve motor function. It can significantly improve quality of life for patients. Long-term Use: Over time, the effectiveness of L-DOPA may diminish, and patients may experience fluctuations in its effectiveness (known as “on-off” phenomena) and involuntary movements (dyskinesias)
what is Parkinson’s disease
its characterised as a movement and non movement disorder compromising the 4 cardinal symptoms/ clinical presentations (bradykinesis, rigidity, resting tremor, postural instability-occurs later), and non motor features such as sleep disorder-RBD, constipation, depression/anxiety, loss of smell, pain
overview of PD pathology?
loss of dopaminerifc neurones in sybstatia nigra
loss of dopamine in striatum
progressive and asymmetrical
responsiveness to L-dopa
Presence of Lewy bodies- aggregate of a-synuclein and is intracellular
what scans can be done to view level of dopmaine in brain
DAT scan
Why are dopaminergic neutrons susceptible in PD?
Understanding why dopaminergic neurones are vulnerable to PD. They don’t know but an idea proposed that they’re highly metabolically active.
–> High Metabolic Demand: Dopaminergic neurons in the substantia nigra have long, extensively branched axons. Maintaining these extensive networks requires a lot of energy, which results in high metabolic activity. This high energy demand makes them particularly susceptible to any disruptions in mitochondrial function, leading to increased oxidative stress.canaffect the trasnports that are enegery dependednt
–> Oxidative Stress from Dopamine Metabolism: Dopamine itself, while essential for normal brain function, can be cytotoxic if not properly managed. When dopamine is released but not immediately reabsorbed or broken down, it can undergo auto-oxidation, leading to the formation of reactive oxygen species (ROS) and quinones. These reactive molecules can damage cellular components, including proteins, lipids, and DNA.
–> Dopamine Packaging and Transport: To mitigate the cytotoxic effects of dopamine, dopaminergic neurons rapidly reuptake released dopamine from the synaptic cleft using dopamine active transporters. The dopamine is then packed into synaptic vesicles by vesicular monoamine transporter 2 (VMAT2). This packaging not only prevents dopamine from being oxidized but also ensures its availability for future neurotransmission. Any dysfunction in these transport mechanisms can lead to increased levels of free dopamine and, consequently, higher oxidative stress.
–> Mouse brain- VTA is positioned next to nigral regions and are unaffected in PD. So it’s interesting how those regions are protected. The theorised reason for this is because in nigra neurones they have high DAT expression level so they can recover dopamine released into striatum very quickly but have very low VMAT2 levels so once its into cell it’s not good at repackaging it. On the hand the VTA neurone have the opposite low DAT levels so much controlled and slower but have high VMAT2 levels
describe lewy body pathology and where are they located in the neurons and what is their role?
aggregates composed of AS which are inclsuions
present sporadic or genetic PD
stain for ubiquitin and AS
sits at the presynaptic termina (possibly has a role in synaptic
release and reuptake- they aren’t sure). Having mutations in A-synuclein genes (such as SNCA) gives familial types of PD with early onset
genetics of PD (SNCA)
These are some mutations. the type of mutation determines the onset.
Can have duplication or triplication of Alpha synuclein locus, increases amount of synuclein that you would have in the brain.
Duplication -onset early 50s- 3 copies of protien expression
Triplication- onset early 40s - 4 copies of protien expression
what is the most commonly mutated gene in PD and what is its mechanism of action?
LRRK2 is a gene that’s affected in PD- most commonly mutated
Alpha-synuclein mutations above is quite rare (3/4 families in entire world would probably have this).
Muhammed Ali carried this gene
Mutations in LRRK2 often increase its kinase activity, leading to hyperphosphorylation of various substrates. This abnormal phosphorylation can impair cellular functions and lead to neuronal damage and death.
LRRK2 mutations have been linked to mitochondrial dysfunction. Mitochondria are the powerhouses of the cell, and their impairment can lead to reduced energy production and increased oxidative stress, contributing to the death of dopaminergic neurons in the substantia nigra
Mutations in LRRK2 can disrupt this process, leading to the accumulation of undegraded proteins and organelles, including α-synuclein, a protein that forms toxic aggregates in PD.
Mutations can activate these cells abnormally, leading to neuroinflammation and exacerbating neuronal damage
mutation of PINK1 and PARKIN
there is a loss of function mutation in these genes which affects the process of mitophagy which is the selective removal of damaged mitochondria. mutations in these genes impairs this function and causes early onset PD
mutation in GBA
GBA encodes for the GCase enzyme. loss of function mutation means that there is less expression/actiivty of this enzyme. this impairs the trafficking of the lysosome for the final stage of autophay needed for the breakdown of AS, as a result there is accumulation of AS.
mutation in SCNA
increases amount of AS
how do we study neurodegenerative diseases?
mouse models (transgenetic-models for gain of fucntion/ dominant mutations or knock out- modesl fro loss of fucntion- recessive mutation)
helps with theraputic targets by creatng a model for early-stage disease
study progession of disease over time
mouse lives 2 years, not 80 years (Not suitable for late-stage disease)
you can see physiological changes over time
what are the different models that can be used to study neurodegenrative diseases?
transgenic/ knock out mice
gene expression in post-mortem brain tissue
inuced pluripotnet models
what is the difference between genetic and sporadic forms of PD?
Sporadic Parkinson’s Disease
Prevalence: The vast majority of Parkinson’s disease cases are sporadic, accounting for about 90% or more of all cases.
Causes: The exact cause is unknown, but it is believed to result from a combination of environmental factors, lifestyle factors, and aging, with possible contributions from genetic susceptibility that does not follow a clear pattern of inheritance.
Onset: Typically occurs later in life, with most diagnoses made in people over the age of 60.
Symptoms and Progression: Symptoms and disease progression can vary widely among individuals.
Genetic Contribution: While not directly caused by specific genetic mutations, certain genetic variants may increase the risk or susceptibility to developing sporadic PD.
Genetic Parkinson’s Disease
Prevalence: Makes up a small percentage of all PD cases, estimated at about 10% or less.
Causes: Caused by specific genetic mutations that are inherited from one’s parents. Mutations in several genes, such as LRRK2, SNCA (which encodes alpha-synuclein), Parkin, PINK1 have been linked to familial forms of PD.
Onset: Can occur at a younger age than sporadic cases, with some forms of genetic PD appearing in individuals under 40 or 50 years old.
Symptoms and Progression: The symptoms can be similar to sporadic PD, but the age of onset and rate of progression can vary depending on the specific mutation. Some genetic forms of PD may have distinct clinical features or respond differently to treatments.
Inheritance Patterns: The inheritance patterns can be autosomal dominant (where only one copy of the mutated gene, inherited from one parent, is sufficient to increase the risk of developing the disease) or autosomal recessive (where two copies of the mutated gene, one inherited from each parent, are necessary to significantly increase the risk).
in both forms, the underlying pathophysiology involves the loss of dopaminergic neurons in the substantia nigra and the accumulation of alpha-synuclein containing Lewy bodies, leading to the hallmark motor and non-motor symptoms of Parkinson’s disease.
what is the most common genetic risk factor for PD?
LRRK2 and GBA
