PSYC 211 Lecture 21: Neurodegenerative Diseases

Introduction to Behavioral Neuroscience

• Course name: PSYC 211
• Lecture: 21 of 24
• Topic: Neurodegenerative Diseases
• Textbook Chapter: 15 (continued)
• Instructor: Jonathan Britt
• Email: [email protected]

Neurodegenerative Disorders

• Many types exist, including Alzheimer's, Parkinson's, Huntington's, FTD-ALS, and prion diseases.
• Some conditions affect specific cell types, while others cause widespread degeneration.
• Neuronal degeneration is driven by cellular apoptosis, triggered when misfolded proteins clump, disrupting normal function.
• All proteins have a risk of clumping at high concentrations.
• Evolution favors proteins resistant to clumping.
• Cells have mechanisms to ensure correct protein folding and destroy misfolded proteins, but struggle with protein aggregate removal.

Prion Protein Disease

• Contagious, causing widespread brain degeneration (spongiform encephalopathy).
• Includes mad cow and Creutzfeldt-Jacob disease.
• Accumulation of misfolded prion protein causes misfolding in other proteins, spreading throughout the brain.
• Prion diseases spread through contact with misfolded prion protein (cell to cell, animal to animal).
• Death typically within one year.
• Unique infectious agent: protein only, unlike other infectious agents that contain nucleic acids.

Huntington's Disease

• Neurodegenerative disease with clear genetic basis.
• Affects 1 in 10,000 people.
• Caused by a mutation in the Huntingtin gene, resulting in misfolded huntingtin protein.
• Huntingtin protein is highly expressed in the basal ganglia.
• Protein aggregation leads to basal ganglia degeneration.
• Onset typically between 30 and 50 years old, with death following 15-20 years later.
• Symptoms include increasing lack of coordination, jerky movements, and eventually dementia.

Antisense Therapy

• No current cure or treatment for neurodegenerative diseases, although there's potential for antisense gene therapy.
• Researchers administer antisense DNA/RNA into the spinal cord to complement mRNA and prevent translation into protein in hopes of altering gene expression
• Large clinical trials have recently failed.

Parkinson's Disease

• Degenerative movement disorder, less obviously genetic compared to other examples.
• Degeneration of dopamine neurons in the substantia nigra of the midbrain.
• Misfolded alpha-synuclein protein aggregates remain.
• Common, affecting 1% of the population usually after 60.
• Reduced dopamine signaling causes muscle rigidity, slow movement, shaking, difficulty walking, and eventually dementia.
• No cure but treatments for motor symptoms exist.

Parkinson's Disease (continued)

• Alpha-synuclein protein is highly expressed in dopamine neurons in the midbrain.
• Abnormal accumulation is associated with dopamine neuron degeneration.
• Lewy bodies, aggregates of misfolded alpha-synuclein protein, are found in the cytoplasm of midbrain dopamine neurons.
• Rare mutations in the alpha-synuclein gene can promote Lewy body formation.
• Ubiquitin is added to faulty proteins to target them for breakdown by proteasomes.
• Parkin is a critical protein for ubiquitination. Mutated parkin can lead to familial Parkinson's.
• Defective parkin allows misfolded proteins to aggregate and kill cells.
• Dopaminergic neurons are especially vulnerable to parkin and alpha-synuclein dysfunction.

Parkinson's Disease (continued)

• Toxic gain of function: dominant gene mutations producing toxic proteins (e.g. preventing ubiquitination of alpha-synuclein).
• Loss of function: recessive gene mutations resulting in the absence of a necessary protein (e.g., parkin gene mutations).

Parkinson's Disease Treatment

• Dopamine signaling elevation alleviates motor symptoms.
• Dopamine receptor agonists, despite some effectiveness, tend to have side effects.
• Precursors like L-dopa can cross the blood-brain barrier to be converted into dopamine, offering temporary symptom relief.
• Deep brain stimulation (DBS) can improve motor symptoms by targeting overactive brain regions (globus pallidus, subthalamic nucleus)

Dementia

• Progressive impairment of memory, thinking, and behavior impacting daily activities.
• Common causes include neurodegenerative diseases, multiple strokes, and repeated brain trauma.

Alzheimer's Disease

• Neurodegenerative disorder that causes progressive memory loss, motor deficits, and eventual death.
• Common in individuals 65+ and higher prevalence in individuals older than 90.
• Associated with misfolded amyloid protein aggregates and severe degeneration in the hippocampus and neocortex.

Alzheimer's Disease (more detail)

• Amyloid plaques (extracellular aggregates of misfolded amyloid protein).
• Tau protein (microtubule protein hyper-phosphorylated in Alzheimer's, disrupting intracellular transport).
• Neurofibrillary tangles (intracellular accumulation of twisted Tau protein in dying neurons).
• Amyloid precursor protein (APP) is a precursor to the amyloid involved, located on chromosome 21 (duplicated in Down Syndrome).
• Secretases cut amyloid precursor protein into fragments; mutations in secretases like presenilin can cause problems.

Alzheimer's Disease (additional elements)

• Apolipoprotein E (ApoE) a glycoprotein that transports cholesterol and plays a role in cellular repair.
• Having the E4 allele of ApoE increases Alzheimer's risk.
• Traumatic brain injury is a significant risk factor, alongside obesity, hypertension, diabetes, and high cholesterol.
• Well-educated individuals tend to show lower prevalence and actively maintaining their minds and bodies.

Alzheimer's Disease Treatment

• No known cure presently; medications may reduce symptoms but do not stop neurodegeneration.
• Immunotherapy, where antibodies are injected to target and destroy amyloid and Tau proteins, shows promise, with more than 100 clinical trials underway.

ALS-FTD

• Form of neurodegenerative disorder affecting motor neurons.
• Attacks motor neurons in the spinal cord and cranial nerves.
• Symptoms include spasticity, exaggerated reflexes, weakness, muscle atrophy, eventually leading to paralysis and death.
• Mostly sporadic (unknown cause), though some cases are inherited.
• Incidence is relatively low, but some individuals live longer.
• ALS and frontotemporal dementia (FTD) are now considered parts of a common spectrum.

Common but Harmful Gene Variants

• Prion disease, Huntington's, and ALS-FTD are relatively rare.
• Parkinson's and Alzheimer's are relatively common.
• Heart disease, strokes, and cancer are common.
• Each of these conditions has a genetic component.
• Common gene variants exist that slightly increase risk.

Reproductive Success

• A significant percentage of both men and women never have children.
• Physical and mental health can significantly reduce reproductive success.
• Genes that increase risk for disease might seem selectively unfavorable but still exist due to gene-environment interaction.

Genetic Variation

• Gene mutations arise each generation.
• Mutations create different versions of a gene or its promoter regions (alleles).
• Common alleles are present in more than 1% of the human population.
• If over 1% of population have allele, likely not uniformly detrimental, or else rare.
• Equally unlikely for allele to uniformly beneficial; if so everyone would have it.

Bad Genes

• Natural selection removes harmful genes across generations.
• Harmful mutations are rare and recent in origin.
• Slightly harmful gene mutations persist across generations, possibly due to origin

Good Genes

• Beneficial alleles become more prevalent as harmful alleles are removed.
• "Fixation" occurs when an allele reaches nearly 100% prevalence in a population.
• Fixation generally takes significantly less time than harmful genes persistance.
• Rapid evolutionary changes in human history are potentially visible in recent phenotypic adaptations.

Genetic Basis of Disease

• Analyzing genomes shows common alleles that increase disease risk.
• Evolutionary pressure suggests that common disease genes possibly had benefit previously (or might still in some environments) under different conditions

Gene-Environment Interactions

• Environment stability leads to alleles persistence that are beneficial or neutral under those circumstances.
• Alleles that were previously neutral might become harmful.
• Gene-environment interactions occur where an allele’s effect is neutral in one context but not in another—an important driver for current human issues including obesity, diabetes, asthma, addiction, heart disease, strokes, cancer, late-onset dementia/neurodegeneration and depression/anxiety.

Mental Illness

• Some mental illnesses show less clear gene-environment interactions (e.g. schizophrenia)
• However, severe mental illnesses tend to exhibit heritability and decreased reproductive success.
• While genetic, why remain prevalent if reproductive success is at least slightly impacted?

This quiz covers Lecture 21 of PSYC 211, focusing on neurodegenerative diseases such as Alzheimer's, Parkinson's, and prion diseases. Understand the mechanisms of neuronal degeneration, including protein misfolding and apoptosis. Explore the impact of these disorders on cellular function and treatment challenges.