Lecture Summaries

WEEK # TOPICS LECTURE SUMMARIES
1 Introduction The students and instructor will introduce themselves and review the course syllabus and objectives. An introductory talk will be given about the model organisms and genetic techniques that will be discussed during the course.
2 Parkinson's disease I Parkinson's disease (PD) is a degenerative disorder involving loss of dopamine-producing neurons in a region of the brain called the substantia nigra. Intracellular aggregation of the protein α-synuclein is a major hallmark of PD, and much research has been dedicated to investigating if and how these aggregates contribute to toxicity and neuronal cell death. We will discuss how simple overexpression systems can be employed to recapitulate α-synuclein aggregation and explore the molecular mechanisms underlying this feature of PD pathogenesis.
3 Parkinson's disease II We will discuss recent evidence implicating defective protein degradation pathways in PD pathogenesis. Both of the papers discussed today use indirect methods (injection of a toxin and a genetic background that impairs autophagy) to model aspects of PD phenotypes. We will also briefly discuss the oral presentation assignment, which is related to protein degradation pathways in PD, at the end of class today.
4 Alzheimer's disease Alzheimer's disease (AD) is a degenerative brain disorder that is characterized by deposition of Aβ peptides in extracellular amyloid plaques and by aggregation of hyper-phosphorylated Tau into neurofibrillary aggregates in neurons. We will discuss overexpression systems of C. elegans and zebrafish that recapitulate each of these pathologies.
5 Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in the progressive degeneration of motor neurons. The most common familial form of ALS is caused by mutations in superoxide dismutase 1 (SOD1), and the disease is typically modeled by overexpression of mutant SOD1. We will discuss recent work that implicates Ephirns and their receptors in ALS pathogenesis.
6 Lab visit - Huntington's disease model in Drosophila We will visit the laboratory of Professor Troy Littleton in the MIT Picower Institute for Learning and Memory. We will have a brief tour of the lab and attend a presentation about polyglutamine diseases and the lab's Drosophila model of Huntington’s disease.
7 Rett Syndrome Rett Syndrome is an X-linked developmental disorder of the nervous system that primarily affects heterozygous females. It is characterized by apparently normal early development followed by rapid regression, resulting in severely impaired language and motor skills. Rett syndrome is linked to loss-of-function mutations in MECP2 (methyl-CpG-binding protein-2), a transcriptional regulator that binds methylated DNA. Today we will discuss techniques for creating loss-of-function models of MECP2 in mouse.
8 Fragile X Syndrome Fragile X Syndrome (FXS) is a heritable form of intellectual disability resulting from mutation of the fragile X mental retardation gene (FMR1). The fragile X protein (FMRP) is a postsynaptic mRNA-binding protein involved in translational regulation at synapses. The absence of FMRP is thought to result in unregulated synthesis of proteins, with severe consequences for the regulation of synaptic activity. We will discuss mouse knock-out and fly overexpression models of FXS.
9 Deafness and Blindness This week we discuss genetic models of two heritable diseases affecting hearing and vision. Usher syndrome I results in severe hearing loss and visual impairment and is associated with mutations in several genes that regulate the development and maintenance of hair cells in the inner ear, as well as the development of the retina. Retinitis pigmentosa is a degenerative eye disorder. It is associated with Usher syndeome, but can also occur independently and has been linked to mutations in many genes, including the epithelial membrane protein Crumbs. Loss-of-function models have been established to explore the function of these disease-linked genes in simple organisms.
10 Sleep Disorders Sleep is still a poorly understood phenomenon, but we do know that it is regulated genetically. Today we will discuss two studies that approach sleep research in opposite ways: by creating targeted mutations in a gene linked to a sleep disorder, or by characterizing sleep behavior to screen for genes that affect that behavior.
11 Wound Healing Epithelial sheets line the surfaces of the body, forming an essential barrier between the external environment and internal tissues. Wound detection and wound healing are important programs to restore epithelial integrity following injury. Researchers study this phenomenon in simple organisms by damaging the epidermis and following its recovery in a variety of genetic or environmental contexts.
12 Addiction An individual's vulnerability to addiction is influenced by genetics. Simple organisms have been developed as useful model systems to identify genes that regulate behavioral responses to addictive substances.
13 Metastasis We will discuss the power of genetic screens for identifying pathways involved in cancer and metastasis.
14 Oral presentations and course discussion

Mutations in ATP13A2 (PARK9) cause an autosomal recessive form of parkinsonism called Kufor-Rakeb Syndrome (KRS). ATP13A2 is a lysosomal membrane protein of unknown function. To date, analysis of ATP13A2 function has been carried out in vitro using human fibroblasts from patients with KRS or shRNA knockdown of ATP13A2 in mouse primary neurons. These analyses showed that loss of ATP13A2 leads to impaired lysosomal degradation and a subsequent accumulation of α-synuclein and toxicity in primary cortical neurons.

You would like to establish an in vivo model to study how ATP13A2 functions and/or how loss of ATP13A2 contributes to PD pathogenesis. Using the strategies that we have discussed during the course, select one simple organism to study and suggest three experiments to begin building this model.

Each student will give a 15-minute oral presentation about her/his proposed experiments to investigate the function of ATP13A2 (PARK9) in vivo. Students will also provide a 1-page handout summarizing his/her proposal.