Functions and Dysfunctions of Protein Processing

Question 1

What is the difference between Familial and Sporadic Neurodegenerative Disorders?

Answer 1

Familial - arise from inherited mutations in specific genes, represent early onset form of the disease
Sporadic- no known cause of disease, represent late onset form of disease; brain aging is common denominator

Question 2

Symptoms, biochemical features and neuropatholgy of Parkinson’s Disease (PD)

Answer 2

Symptoms: Rigidity or stiffness, tremors/shaking hands/legs, slow movement, difficulty with balance, speech and coordination, progressively worsens
Treatment: Dopamine replacement therapy (L-dopa)
Biochemical Features:
- caused by aggregation of protein alpha-synuclein (AS)
-14 kDa protein (cytosolic and bound to plasma membrane
- aggregates to form oligomers then later forms insoluble fibrils which deposit as LEWY BODIES in dopaminergic neurons (DA) of the SUBSANTIA NIGRA (SN)
- result: selective death of DA neurons
- symptoms result of decreased production of dopamine
Neuropathology: monomer —> on-pathway oligomer (toxic) (seeding observed- when one forms- attracts more) —> protofibrillar oligomers –> fibril elongation to amyloid fibril

Question 3

Alzheimer’s Disease (AD) and signs/symptoms

Answer 3

most common neurodegenerative disorder and most common form of dementia
memory loss, difficulty completing familiar tasks, confusion with time and place, visual images and spatial relationships, misplacing things, changes in mood and personality

Question 4

Biochemical Hallmarks of Alzheimer’s Disease (AD)

Answer 4

1. Plaques - B-Amyloid Neuritic Plaque - form extracellular
2. Tangles - Neurofibrillary Tangles - form intracellular

• Amyloid precursor protein (APP)- integral membrane protein (110 kDa) cleaved by several proteases (alpha secretase - normal; beta secretase - amyloidogenic)
• Peptide: amyloid beta peptide (A B) is generated (~4.2 kDa) and released into extracellular space
• Misfolding/Aggregation of amyloid beta peptide forms soluble oligomers and insoluble PLAQUES in brain (EXTRAcellular deposits)
• Microtubule bound protein: Tau is hyperphosphorylated and forms neurofibrillary TANGLES (INTRAcellular deposits)

Question 5

Huntington’s Disease

Answer 5

Progressive disorder caused by death of brain neurons - specifically Basal Ganglia and cerebral cortex
Affects: Behavior (psychiatric functioning, motor functioning, cognitive functioning)
Mutation in Huntington gene (HTT) - encodes Huntington protein - important role in brain neurons, involved in signaling, binding to other proteins, protecting neurons from apoptosis, repairing damaged DNA
HTT knock out mouse is lethal

Question 6

Biochemical features of Huntington’s Disease

Answer 6

HTT gene contains CAG trinucleotide repeat (codes for Glutamine)
Expansion of CAG triplet repeats results in HD
10-35 repeats: Normal
40-50 repeats: Adult onset
>60 repeats: Juvenile onset
Polyglutamine repeats in Huntington protein –> intramolecular H bonds —> misfolding and aggregrate formation
Selective death of neurons —> symptoms

Question 7

Neuropathology of Huntington’s Disease

Answer 7

Atrophy of cerebral nerve tissue, striatum, and basal ganglia and ventricular dilation

Question 8

Amyotropic Lateral Sclerosis (ALS)

Answer 8

progressive nervous system disease
affects nerve cells in brain and spinal cord - loss of muscle control
begins with muscle twitching and weakness in limb or slurred speech
eventually affects muscles needed to move, speak, eat and breathe —> death

Question 9

Biochemical features of ALS

Answer 9

mutations in copper zinc superoxide dismutase (CuZn) - cytosolic enzyme responsible for dismutation of superoxide anion to hydrogen peroxide
mutations in SOD cause GAIN OF FUNCTION
forms reactive oxygen species (ROS) and induces oxidative stress
activates cell death pathways
SOD deposits/aggregates