Protein Misfolding Flashcards
What are the consequences of protein misfolding?
Causes generation of ROS, increase oxidative stress, disrupt neuronal signaling, disturb, ion homeostasis, Ca regulation, disrupt energy homeostasis, inflammation, damage organelles, break plasma membrane and cause cell death
What does neurodegeneration correspond to?
Any pathological condition primarily affecting neurons
Neurodegenerative disorders present what?
A large group of neurological disorders with heterogenous clinical pathological expressions
Affect specific subsets of neurons in specific functional regions of the brain
What is the common denominator in neurodegenerative disorders?
Involve misfolding of proteins
What are familial neurodegenerative disorders?
Mutations arising in specific genes
Represent early onset form of the disease
What is a sporadic form of a neurodegenerative disorder?
No known cause
Represent late onset form of the disease
Brain aging is the common denominator
What is the most common neurodegenerative disorder and the most common form of dementia?
Alzheimer’s disease
What forms the insoluble plaques seen in Alzheimer’s disease?
Misfolding/aggregation of amyloid beta forms soluble oligomers and insoluble plaques in the brain (extracellular deposits)
What causes the neurofibrillary tangles seen in Alzheimer’s?
A microtubule bound protein called Tau becomes hyper-phosphorylated and forms the tangles (intracellular deposits)
What is the hallmark for Alzheimer’s disease?
Insoluble plaques and neurofibrillary tangles
Overall shrinkage of the brain and atrophy of the temporal lobe impacting memory and language
What are the early sx of Alzheimer’s?
Memory loss, confusion with time or place, trouble understanding visual images and spatial relationship, mismatching things, and changes in mood and personality
What are sx of Parkinson’s disease?
Tremors, rigidity or stiffness, difficulties with balance, speech and coordination
What are the biochemical features of Parkinson’s disease?
Caused by aggregation of alpha synuclein protein
Aggregates to form oligomers and later on insoluble fibrils which deposits as Lewy bodies in dopaminergic neurons in substantia nigra resulting in their death
Sx due to reduced availability of dopamine
What is the molecular weight of amyloid precursor protein and what is its sub cellular location?
4.2 kDa
Extracellular space
What is the molecular weight of alpha synuclein and where is it located in the cell?
14 kDa
Cytosolic and bound to plasma membrane
What is amyotrophic lateral sclerosis (ALS)?
Progressive NS disease that affects the nerves in the brain and spinal cord causing loss of muscle control
Also called Lou Gehrig’s disease
What are some sx of ALS?
Often begins with muscle twitching and weakness in a limb or slurred speech
Eventually affects control of the muscles needed to move, speak, eat and breathe
No cure and cause is unknown
What are the biochemical features of ALS?
Mutations in Cu/Zn SOD which is the cytosolic enzyme responsible for dismutation of superoxide anion to H2O2
Mutations in SOD cause gain of function
Forms ROS and induces oxidative stress
What is the molecular weight and cellular location for Cu/Zn SOD?
32 kDa
Cytosol
What is the molecular weight of the Huntingtin protein and what is its location in the cell?
350 kDa
Cytosol and nucleus
What is the function of Huntingtin protein?
Exact function is unknown but it appears to play an important role in nerve cells in the brain and is essential for normal development before birth
Also involved in chemical signaling and protecting the cell from apoptosis
What causes Huntington’s disease?
The HTT gene contains a DNA segment known as the CAG tri-nt repeat which is normally repeated 10-15 times within the gene
Expansion of these repeats leads to HD
Polyglutamine repeats in the abnormal Huntingtin protein forms intramolecular H bonds which eventually misfold and aggregate
What are the three primary aspects of presentation of HD?
Behavior, movement and thinking
What is the inheritance for HD?
Autosomal dominance
Sx of HD
Staggering gait, jerking or abrupt movements, speech too loud or soft, problems multitasking, disorientation, problems with short term memory, irritability, explosive temper, inappropriate sexual behavior
What Tx is currently being considered to for HD?
IONIS-HTT which inhibits mRNA and can lead to a decrease in Huntingtin protein
