degenerative disease Flashcards
what is muscular dystrophy caused by
Recessive X-linked disease
Both sexes may carry the mutation, but females rarely develops signs of the disease (X-linked)
Caused by a mutation in the dystrophin gene (Xp21), the largest gene located on the X chromosome, encoding the protein dystrophin.
65% of the causes are due to partial gene deletion. Gene deletion leading to in-frame mutations allows for the coding of partially functional protein. Out of frame mutations leads to prematurely truncated protein that is completely lost.
Explain what u know about duchenne and becker
There are 2 types of muscular dystrophy: Duchenne and Becker.
Becker Muscular Dystrophy (BMD) is caused by the in-frame mutation of the dystrophin gene. This results in a partially functional protein and some bridging function is maintained. This is the milder phenotype and 10-40% of the normal functional proteins are still made.
Duchenne Muscular Dystrophy (DMD) is caused by the out-of-frame mutation of the dystrophin gene, but this leads to a prematurely truncated protein that is completely non-functional, losing all bridging function. This is the severe phenotype.
what is the protein involved in muscular dystrophy and what does it normally do
Dystrophin has actin-binding region that allows it to bridge actin filaments of the cytoskeleton to the ECM, preserving the integrity of muscle fibres
Myosin filaments slide during muscle contraction and need to be anchored to the sarcolemma, which is normally done through dystrophin and linking proteins.
In the absence of dystrophin / with faulty protein, the muscles are not able to contract properly.
muscular dystrophy tretment
Treatments of muscular dystrophy include:
Corticosteroids (like deflazacort - im not going to rmb this shit)
Beta-2 antagonists, which increases muscle strength without affecting disease progression
Mild physical activity and physiotherapy
New drugs like Eteplirsen, which acts to increase dystrophin production in the treatment of DMD.
what is eteplirsen
Eteplirsen (Exondys 51)
In MD, the exon 50 is missing, and the patients have a frameshift mutation in exon 51, resulting in the production of an unstable, non-functional and truncated dystrophin.
MOA: acts by preventing the incorporation of exon-51 in the pre-mRNA into the mature mRNA (exon skipping) and this removes the frameshift defect (now in frame liao). This produces a shorter but somewhat (50%) functional dystrophin, improving symptoms.
what is alzheimer’s
irreversible progressive brain disease
affecting memory and thinking skills
slowing of motor functions
Risk factors for developing Alzheimer’s disease all lead to the amyloid ß deposition.
Mutation in the APP (amyloid precursor protein) gene on chromosome 21
Mutation in apolipoprotein E genes on chromosome 19, this mutation is more common
what are the 3 hypothesis in AD
beta amyloid
tau protein
neuroinflamatoryb
beta amyloid hypothesis
APP is a membrane spanning protein, in AD, it is cleaved into Aß monomers by secretases (enzymes)
Aß aggregates, forming senile plaques which form senile plaque
The monomers alone are non-toxic, but they cannot be recalled into the cells, become toxic, and accumulate surrounding neurons leading to synaptic damage and neuronal cell death
tau protein hypothess
Neurons have internal support structures made up of microtubules, and these are stabilised by tau proteins.
In AD, tau proteins are hyperphosphorylated, and aggregates, forming neurofibrillary tangles (NFT). This leads to the collapse of microtubules.
Cytoskeletal imbalance, resulting in synaptic damage and neuronal death.
neuroinflammatory hypothesis
Following neuronal cell death (possible from Aß hypothesis?), microglial cells are activated to clean up the remains / cell debris
They release pro-inflammatory cytokines, such as IL-1, which leads to neuroinflammation, leading to more neuronal death, cleavage of APP and generation of more Aß monomers, resulting in more synaptic damage.
progression of AD (7 steps)
- ab formation
- neuroinflmamation
- tau protein accumulation
- brain metbaolic dysfunction
- brain strophy
- cognitive decline
- develpoemetn of dementia symptoms
parkinsons
PD is also a progressive disease affecting the nervous system and the parts of the body that are controlled by nerves. Factors such as head injury, toxins, age-related factors and genetic mutations all predispose PD.
do u wanna know the pathogenesis of parkinsons
(Thank you chatgpt) In PD, alpha-synuclein aggregates to form Lewy bodies intracellularly within the dopaminergic neurons in the substantia nigra. This results in neuronal cell damage and death, and the loss of dopaminergic neurons result in decreased dopaminergic neurons. Decreased dopaminergic stimulation of the basal ganglia, and leading to the motor symptoms of PD (bradykinesia). Alpha-synuclein aggregation can also result in mitochondrial dysfunction, and oxidative stress, which leads to the generation of reactive oxidative species (ROS), further contributing to neuronal damage.
tx for parkinsons
Treatment: Levodopa (+ carbidopa), deep brain stimulation and more recently (2023), lixisenatide, semaglutide for early PD.
