Protein Misfolding

Question 1

What are the consequences of protein misfolding?

Answer 1

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

Question 2

What does neurodegeneration correspond to?

Answer 2

Any pathological condition primarily affecting neurons

Question 3

Neurodegenerative disorders present what?

Answer 3

A large group of neurological disorders with heterogenous clinical pathological expressions
Affect specific subsets of neurons in specific functional regions of the brain

Question 4

What is the common denominator in neurodegenerative disorders?

Answer 4

Involve misfolding of proteins

Question 5

What are familial neurodegenerative disorders?

Answer 5

Mutations arising in specific genes

Represent early onset form of the disease

Question 6

What is a sporadic form of a neurodegenerative disorder?

Answer 6

No known cause
Represent late onset form of the disease
Brain aging is the common denominator

Question 7

What is the most common neurodegenerative disorder and the most common form of dementia?

Answer 7

Alzheimer’s disease

Question 8

What forms the insoluble plaques seen in Alzheimer’s disease?

Answer 8

Misfolding/aggregation of amyloid beta forms soluble oligomers and insoluble plaques in the brain (extracellular deposits)

Question 9

What causes the neurofibrillary tangles seen in Alzheimer’s?

Answer 9

A microtubule bound protein called Tau becomes hyper-phosphorylated and forms the tangles (intracellular deposits)

Question 10

What is the hallmark for Alzheimer’s disease?

Answer 10

Insoluble plaques and neurofibrillary tangles

Overall shrinkage of the brain and atrophy of the temporal lobe impacting memory and language

Question 11

What are the early sx of Alzheimer’s?

Answer 11

Memory loss, confusion with time or place, trouble understanding visual images and spatial relationship, mismatching things, and changes in mood and personality

Question 12

What are sx of Parkinson’s disease?

Answer 12

Tremors, rigidity or stiffness, difficulties with balance, speech and coordination

Question 13

What are the biochemical features of Parkinson’s disease?

Answer 13

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

Question 14

What is the molecular weight of amyloid precursor protein and what is its sub cellular location?

Answer 14

4.2 kDa

Extracellular space

Question 15

What is the molecular weight of alpha synuclein and where is it located in the cell?

Answer 15

14 kDa

Cytosolic and bound to plasma membrane

Question 16

What is amyotrophic lateral sclerosis (ALS)?

Answer 16

Progressive NS disease that affects the nerves in the brain and spinal cord causing loss of muscle control
Also called Lou Gehrig’s disease

Question 17

What are some sx of ALS?

Answer 17

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

Question 18

What are the biochemical features of ALS?

Answer 18

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

Question 19

What is the molecular weight and cellular location for Cu/Zn SOD?

Answer 19

32 kDa

Cytosol

Question 20

What is the molecular weight of the Huntingtin protein and what is its location in the cell?

Answer 20

350 kDa

Cytosol and nucleus

Question 21

What is the function of Huntingtin protein?

Answer 21

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

Question 22

What causes Huntington’s disease?

Answer 22

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

Question 23

What are the three primary aspects of presentation of HD?

Answer 23

Behavior, movement and thinking

Question 24

What is the inheritance for HD?

Answer 24

Autosomal dominance

Question 25

Sx of HD

Answer 25

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

Question 26

What Tx is currently being considered to for HD?

Answer 26

IONIS-HTT which inhibits mRNA and can lead to a decrease in Huntingtin protein