Introduction To Behavioral Neuroscience Lecture 21 - PDF

Introduction to Behavioral Neuroscience PSYC 211 Lecture 21 of 24 – Neurodegenerative Diseases Textbook Chapter 15 (continued) Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  NEURODEGENERATIVE DI...

Introduction to Behavioral Neuroscience PSYC 211 Lecture 21 of 24 – Neurodegenerative Diseases Textbook Chapter 15 (continued) Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  NEURODEGENERATIVE DISORDERS There are many kinds of neurodegenerative disease, such as Alzheimer's, Parkinson's, Huntington's, FTD-ALS, and prion diseases. Some of these conditions are associated with the degeneration of a particular cell type, while others cause more widespread degeneration. Neuronal degeneration is driven by cellular apoptosis, which is triggered when clumps of misfolded proteins disrupt normal cellular function. At high enough concentrations, all proteins have a risk of clumping together. Evolution has favored proteins that are resistant to clumping. Cells have numerous ways to ensure that proteins fold up into their correct 3-dimensional shape because misfolded proteins have a high probability of clumping together. Cells also have numerous ways of destroying misfolded proteins, but they clearly have a hard time getting rid of aggregates of misfolded proteins.  PRION PROTEIN DISEASE Transmissible Contagious disease that causes widespread neurodegeneration, spongiform making the brain look like a sponge. encephalopathy Includes mad cow and Creutzfeldt-Jacob disease Accumulation of misfolded prion protein is responsible for transmissible spongiform encephalopathies. Prion Misfolded proteins that can cause other copies of the same protein to misfold, which spreads the problem throughout the brain. When a misfolded prion protein interacts with a correctly folded prion protein, it causes it to misfold as well. Accordingly, prion protein diseases spread from cell and cell and animal to animal by means of contact with misfolded prion protein. Death usually occurs within a year. It is the only infectious agent that is just a protein. All other infectious agents (viruses, bacteria, fungi, parasites) contain nucleic acids (DNA or RNA).  HUNTINGTON’S DISEASE Huntington’s disease is a neurodegenerative disease with a very clear genetic basis. It affects 1 in 10,000 people. It caused by a mutation in the Huntingtin gene, which results in misfolding of the huntingtin protein. This mutation is dominant (you only need one bad copy of the gene). Huntingtin protein is highly expressed in the basal ganglia. Aggregation of this protein causing parts of the basal ganglia to degenerate. Symptoms usually begin between 30 and 50 years of age and death follows 15-20 years later. It is characterized by an increasingly severe lack of coordination, uncontrollable jerky limb movements, and eventually dementia followed by death. Movements in Huntington's disease look like fragments of purposeful movements but occur involuntarily. normal Huntington’s brain disease  ANTISENSE THERAPY There is presently no cure (or treatment). There is some optimism about the potential for antisense gene therapy, but two large clinical trials recently failed. Researchers have been administering antisense DNA (or RNA) into the spinal cord of patients. Antisense DNA complements mRNA, and when they bind together the mRNA does not get translated into protein. Researchers hope that one day this approach (or viral-mediated gene delivery and gene editing technologies) will become a practical and effective approach to altering gene expression in the brains of living people.  PARKINSON’S DISEASE Parkinson’s disease is another degenerative “movement” disorder, but it does not have an obvious genetic basis (in most instances). It results from the degeneration of dopamine neurons in the midbrain, specifically in the substantia nigra. There are typically aggregates of misfolded alpha-synuclein protein left behind. Parkinson’s disease is very common, affecting 1% of the population. Symptoms usually appear after the age of 60. Reduced dopamine signaling in the basal ganglia leads to muscle rigidity, slowness of movement, shaking, difficulty walking, and eventually dementia. Without treatment, people have increasing difficulty initiating purposeful movement. There is presently no cure, but there are many ways to alleviate the motor problems. Cognitive, emotional, and sleep disturbances eventually develop as well, and there are currently no good treatments for these symptoms.  PARKINSON’S DISEASE Alpha-synuclein Protein heavily express in midbrain dopamine neurons. Abnormal accumulations are associated with dopamine neuron degeneration in Parkinson's disease. Lewy body Aggregate of misfolded alpha-synuclein protein found in the cytoplasm of midbrain dopamine neurons in people with Parkinson's disease Rare mutations in the alpha-synuclein gene have been identified that promote the formation of Lewy bodies. These mutations are not present in most cases. PARKINSON’S DISEASE Ubiquitin: Protein that is added to faulty/old/ misfolded proteins, which targets them for degradation. Ubiquitinated proteins get brought to proteasomes, which breaks them into their constituent amino acids for recycling. Parkin: Protein that plays a critical role ubiquitination. Mutated parkin is one cause of familial Parkinson's disease. If parkin is defective, misfolded proteins accumulate, aggregate, and eventually kill the cell. Proteasome: Organelle responsible for destroying ubiquitinated proteins within a cell. Dopaminergic neurons are especially sensitive to loss of parkin function and alpha-synuclein aggregation.  PARKINSON’S DISEASE Toxic gain of When a dominant gene mutation produces a protein with toxic effects function Examples: Mutations in the alpha-synuclein gene can prevent the protein, when misfolded, from being ubiquitinated (resulting in Parkinson’s Disease). Mutations in the huntingtin gene can cause the huntingtin protein to misfold (resulting in Huntingtin’s disease). Loss of A recessive gene mutation that when present on both chromosomes function results in the absence of a necessary protein. Example: Loss of function mutations in the parkin gene can make it unable to ubiquitinate misfolded alpha-synuclein protein.  PARKINSON’S DISEASE Treatment Elevating dopamine signaling in the brain alleviates the motor symptoms of Parkinson’s Disease (for many years). Dopamine receptor agonists work to some extent, but they cause too many side effects (in the peripheral nervous system). Dopamine does not cross the blood-brain barrier, but a precursor of dopamine (L- dopa) can enter the brain where it is readily converted to dopamine. Daily administration of L-dopa can diminish the motor symptoms for many years. Brain lesions and deep brain stimulation (DBS) are also common treatments. The main targets for lesions and DBS are parts of the basal ganglia that become overactive in PD: the globus pallidus and subthalamic nucleus. Damaging the globus pallidus or disrupting subthalamic nucleus activity seems to relieve symptoms of Parkinson's disease by removing one of the brakes on motor behaviour.  DEEP BRAIN STIMULATION (DBS)  DEGENERATIVE DISORDERS Dementia Progressive impairments to memory, thinking, and behavior due to a neurological disorder that affect one’s ability to perform everyday activities Common causes are neurodegenerative disease, MS, multiple strokes, and repeated brain trauma.  ALZHEIMER'S DISEASE Alzheimer’s disease is a neurodegenerative disorder that causes progressive memory loss, motor deficits, and eventually death. It occurs in approximately 10 percent of the population above the age of 65 and almost 30 percent of people older than 90 years It is associated with aggregates of misfolded -amyloid protein and severe degeneration within and around the hippocampus and neocortex.  ALZHEIMER'S DISEASE -amyloid (A) Aggregates of misfolded -amyloid protein are present in the brains of people with Alzheimer's disease Amyloid Extracellular aggregation of -amyloid protein surrounded by plaque glial cells and degenerating neurons Tau protein Microtubule protein that becomes hyper-phosphorylated in Alzheimer's disease, disrupting intracellular transport. Neurofibrillary Intracellular accumulation of twisted Tau protein in dying tangle neurons ALZHEIMER'S DISEASE amyloid plaque neurofibrillary tangles ALZHEIMER'S DISEASE -amyloid Protein that is the precursor for precursor -amyloid protein. protein The gene for this protein is (APP) located on chromosome 21, which is the one duplicated (triplicated) in down syndrome. Secretase Class of enzymes that cut the - amyloid precursor protein into smaller fragments, including - amyloid  ALZHEIMER'S DISEASE Presenilin Protein that forms part of the secretases that cut APP. Mutations in presenilin can cause it to preferentially generate the abnormal long form of -amyloid, which causes early onset Alzheimer's disease. Apolipoprotein Glycoprotein that transports cholesterol in the blood and plays E (ApoE) a role in cellular repair Presence of the E4 allele of the apoE gene increases risk of late-onset Alzheimer's disease  ALZHEIMER'S DISEASE Other than age, the strongest risk factor for Alzheimer’s disease is traumatic brain injury. Other risk factors include obesity, hypertension, diabetes, and high cholesterol levels. Alzheimer's disease is less prevalent in well-educated people, especially those that keep their minds and body highly active. There is no cure for Alzheimer's Disease. Some medications reduce the symptoms a bit, but they don’t significantly stop the neurodegeneration. There are over 100 clinical trials underway testing new potential treatments. The most promising ones are a form of immunotherapy, in which we inject antibodies that directly bind to A protein or Tau protein, marking them for destruction by the immune system.  ALS-FTD Amyotrophic lateral sclerosis (ALS) – also known as Lou Gehrig’s Disease and motor neuron disease is another type of neurodegenerative disorder. ALS attacks motor neurons in both the spinal cord and cranial nerves. Symptoms include spasticity (increased muscle tension causing stiff, awkward movements), exaggerated stretch reflexes, progressive weakness and muscular atrophy, followed by paralysis and then death. 90% of cases are sporadic (unknown cause), while 10% are inherited from parents. In rare cases, simple gene mutations are the dominant cause. There is currently no cure. Incidence of this disease is approximately 3 in 100,000. The disease typically starts after the age of 50. Life span following a diagnosis is typically 2-4 years, but some people live much longer. For example, Stephan Hawking lived with the disease for over 50 years. ALS and frontotemporal dementia (FTD - another neurodegenerative disorder) are now considered to be part of a common disease spectrum (FTD–ALS) because of genetic, clinical, and pathological similarities.  COMMON BUT HARMFUL GENE VARIANTS Prion disease, Huntington’s disease, and ALS-FTD are somewhat rare. But Parkinson’s and Alzheimer’s are common. Heart disease, strokes, and cancer are common. There is a strong genetic component to all of these conditions. – There are common gene variants in the human population that increase people’s risk. Why have these harmful gene variants not been eliminated through evolution? What are they so common?  REPRODUCTIVE SUCCESS It is estimated that nearly 15% of woman and 40% of men never have a biological child. It is not exactly random who has children. Physical and mental health issues clearly impact people’s likelihood of having kids. It can be hard to classify who exactly has a “severe” mental illness, but researchers estimate that about 4% of the population does, and the fertility rate for this group is about half the national average. Thus, having a “severe” mental illness dramatically reduces reproductive success. According to the theory of evolution and natural selection, gene variants that increase your risk of developing a severe physical or mental health issue should get eliminated from the gene pool across generations. Yet, there seems to be a genetic a basis for nearly every disease and disorder that plagues humanity. How does this make sense?  GENETIC VARIATION Gene mutations arise with each generation. Gene mutations result in there being either different versions of a gene or different versions of a gene promoter region. In either case, we say there are multiple alleles (multiple versions) of that gene. There are tons of different alleles in the human population that are relatively common. By relatively common, I mean more than 1 in 100 people have the allele, rather than 1 in 10,000 people. If more than 1% of the population has a specific allele (a specific gene variant), … it is unlikely that allele is uniformly detrimental to reproductive success (or else why would so many people have it). It is also unlikely that allele is uniformly beneficial to reproductive success (or else why wouldn’t everyone have it).  BAD GENES Natural selection eliminates harmful genes from the gene pool over time. Very harmful gene mutations get quickly eliminated. They are rarely passed down across multiple generations given they greatly reduce reproductive success. Accordingly, very harmful gene mutations tend to be rare and recent in origin. They arise anew with each generation but quickly get selected out. Slightly harmful gene mutations get eliminated more slowly. They tend to be inherited across multiple generations (e.g., from great grandparents). Accordingly, these gene mutations are common in the human population and old in origin. Still, they are unlikely to persist in the gene pool forever. Gene mutations that slightly reduce reproductive success (say by 1%) would only persist in the human gene pool for a hundred generations or so (a few thousand years) before being selected out.  GOOD GENES As harmful alleles get eliminated, the prevalence of beneficial alleles increases until everyone gets them. We say a gene has gone to fixation when the same version is found in (nearly) 100% of the population. If an allele slightly increases reproductive success (say by 1%), it should spread to the entire population within 100 generations or so (a few thousand years for humans). If evolution is this fast, can we see evidence of it in recent human history? When humans spread into different environmental niches over the last 50,000 years, they experienced rapid changes in skin color, facial characteristics, body shapes, and hair types, among other things. The genes mutations associated with these changes spread to everyone and went to fixation (within isolated populations) within five thousand years or so. In general, most genes in the human genome have gone to fixation (virtually 100% prevalence in the human population) because they promoted survival and reproduction in ancestral conditions better than other gene variants did. Such genes comprise the species-typical human genome, and its normal neurodevelopmental product is human nature.  GENETIC BASIS OF DISEASE When we analyze the genomes of people letter by letter (nucleotide by nucleotide), we see a variety of alleles (different version of a gene) that are quite common. Some alleles confer an increased risk of developing a disease or disorder, while other alleles are protective. There is now strong evolutionary pressure acting on these gene variants. A hundred generations from now, if our environment and lifestyle remain unchanged, the good genes will go to fixation as bad genes get selected out. But why are harmful gene variants so common today? How did these problematic genes persist over the last 200,000 years (10,000 generations) of human history? The main factor is that our environment and lifestyles have changed very quickly and very dramatically in recent history. Stone age Agriculture Industrialization 2.5 million 12,000 300 years ago years ago years ago  GENE-ENVIRONMENT INTERACTIONS When the environment is stable for hundreds of generations, the only alleles that are maintained are the ones that are beneficial or completely neutral (in that environment). The prevalence of neutral alleles drifts randomly across generations, since these variations neither help nor hurt reproductive success overall. Clearly, many alleles that were neutral or beneficial 50 generations ago are no longer so. They are now harmful, and there is no clear offsetting benefit of them. When an allele is neutral in one environment but not another, we say there is a gene- environment interaction. Many of the gene variants that are currently associated with disease show the classic hallmarks of gene-environment interactions. These genes are common in the human population, but the prevalence rates of the associated diseases vary widely across cultures and recent history. In many cases, there are obvious, straightforward environmental explanations for the variability in the prevalence of these diseases.  GENE-ENVIRONMENT INTERACTIONS The prevalence rates of the following disorders vary widely across cultures and recent history, and the environmental risk factors associated with them were not present in ancestral environments:  obesity and diabetes (the sudden abundance of cheap, unnaturally delicious food)  asthma (sudden changes in air quality with exposure to pollutants and antigens)  drug addiction (sudden abundance of highly purified synthetic drugs)  heart disease, strokes and cancer (sudden changes in lifespan, diet, and lifestyle).  late onset neurodegenerative disorders (sudden changes in lifespan, diet, and lifestyle).  depression and anxiety (sudden change in lifestyle, although exactly what is unclear)  MENTAL ILLNESS Some mental disorders do not show the classic hallmarks of gene-environment interactions. For example, schizophrenia and autism are clearly heritable, but prevalence rates do not vary widely across cultures or recent history (as far as we can tell). “Severe” mental disorders… – reduce reproductive success (they have half as many children as other people) – are clearly heritable (genetics explains much of the variance in diagnoses) – are very common (about 4% of the population) “Severe” mental illnesses are genetic disorders, but the associated alleles are widespread and seemingly not being eliminated through natural selection. What is going on? Why are harmful, heritable mental disorders so common and why do they persist?