Lecture

SOD1 Pathology: Mechanisms and Implications

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In course

BIO-480: Neuroscience: from molecular mechanisms to disease

The goal of the course is to guide students through the essential aspects of molecular neuroscience and neurodegenerative diseases. The student will gain the ability to dissect the molecular basis of disease in the nervous system in order to begin to under ...

Description

This lecture delves into the genetic causes of ALS, focusing on SOD1 mutations which account for 2% of cases. It explores the toxic gain of function resulting from over 140 SOD1 mutations, the aberrant redox chemistry, protein misfolding, and aggregation. The discussion extends to the non-cell autonomous nature of the disease, challenging the traditional view of cell autonomy in neurodegenerative disorders. Experimental models, such as in vitro and in vivo studies, shed light on the mechanisms of cellular toxicity induced by mutated SOD1. The lecture also covers the implications of ER stress, mitochondrial dysfunction, and excitotoxicity in ALS pathology, emphasizing the intricate interplay between mutated SOD1 and various cell types in disease progression.

Instructors (4)

Hilal Lashuel

2012-2013 Visiting Professor, Standford University. Stanford School of Medicine 2011- Associate Professor of Life Sciences-Brain Mind Institute-EPFL Dir. Laboratory of Chemical Biology of Neurodegeneration 2005-2011 Assistant Professor of Life Sciences-Brain Mind Institute-EPFL Dir. Laboratory of Molecular Neurobiology and Neuroproteomics 2005-2008 Director- EPFL Proteomic Core Facility 2002-2004 Instructor of Neurology- Harvard Medical School and Brigham and Women's Hospital 2001-2002 Sabbatical Fellow- Laboratory for Drug Discovery in Neurodegeneration Harvard Medical School, 2001-2002 Post-doctoral Fellow- Center for Neurologic Diseases Harvard Medical School and Brigham and Women's Hospital Advisor- Prof. Peter T. Lansbury 2000-2001 Research Scientist, The Picower Institute for Medical Research, Great Neck New York 1994-2000 PhD Student; Texas A&M University and the Scripps Research Institute Advisor- Prof. Jeffery W. Kelly 1990-1994 B.S. City University of New York, Brooklyn College Dr. Hilal A. Lashuel received his B.Sc. degree in chemistry from the City University of New York in 1994 and completed his doctoral studies at Texas A&M University and the Scripps Research Institute in 2000. After obtaining his doctoral degree, he became a research fellow at the Picower Institute for Medical Research in Long Island New York. In 2001, he moved to Harvard Medical School and the Brigham and Women's Hospital as a research fellow in the Center for Neurologic Diseases and was later promoted to an instructor in neurology at Harvard Medical School. During his tenure (2001-2004) at Harvard Medical School his work focused on understanding the mechanisms of protein misfolding and fibrillogenesis and the role of these processes in the pathogenesis of Parkinson's and Alzheimer's disease. In 2005 Dr. Lashuel moved Switzerland to join the Brain Mind Institute at the Swiss Federal Institute of Technology Lausanne as a tenure-track assistant professor in neurosciences. Currently, Dr. Lashuel is an associate professor of life sciences and the director of the laboratory of molecular and chemical biology of neurodegeneration. (http://lashuel-lab.epfl.ch/). Research efforts in the Lashuels laboratory focus on understanding the molecular mechanisms of neurodegeneration and developing novel strategies to diagnose and treat neurodegenerative diseases such as Alzheimers and Parkinsons disease. Research in the Lashuel lab is funded by several international funding agencies and foundations, including the Swiss National Science Foundation, European FP7 program (Marie Curie and ERC grants), Human Science Frontiers, Strauss Foundation, Cure the Huntingtons disease foundation and Michael J Fox foundation and is supported by collaborations with pharmaceutical and biotech companies (http://lashuel-lab.epfl.ch/page-50538-en.html), Nestle, Merck-Serono, AC Immune and Johnson and Johnson. Dr. Lashuels research has resulted in the characterization of novel quaternary structure intermediates on the amyloid pathway, identification of potential therapeutic targets, and new hypotheses concerning the mechanisms of pathogenesis in Alzheimers disease, Parkinsons disease and related disorders. Dr. Lashuel scientific contribution to this field includes i) more than100 publications in major peer reviewed journals including Nature journals, Cell, PNAS, JBC, J. Neuroscience JACS, and Angewandtie Chemie; ii) three patents on novel strategies for preventing protein aggregation and treating autoimmune and inflammatory diseases; iii) more than 150 invited lectures since 2002 and more than 5500 citations (7800 citation-Google Scholar) since 1996. Dr. Lashuel has received several pre-doctoral and post-doctoral awards and fellowships and was the recipient of two prestigious awards given to young investigators; Human Science Frontiers young investigator research award and the European Research Council (ERC) starting independent researcher grant and the ERC proof of concept award (2013) These awards provide more than $2.5 Million to Dr. Lashuel to translate some of his ideas and projects into novel strategies for diagnosing and treating neurodegenerative diseases such as Alzheimers and Parkinsons disease. Dr. Lashuel has chaired and co-organized several international conferences and serves as an academic editor for PLoS ONE, an associate editor for frontiers of molecular neuroscience, member of the Editorial advisory board of ChemBioChem and ad hoc reviewer for several international scientific journals and funding agencies.

Official source

Related concepts (31)

Excitotoxicity

In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell.

Proteinopathy

In medicine, proteinopathy ([pref. protein]; -pathy [suff. disease]; proteinopathies pl.; proteinopathic adj), or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way (a toxic gain-of-function) or they can lose their normal function.

Protein folding

Protein folding is the physical process where a protein chain is translated into its native three-dimensional structure, typically a "folded" conformation, by which the protein becomes biologically functional. Via an expeditious and reproducible process, a polypeptide folds into its characteristic three-dimensional structure from a random coil. Each protein exists first as an unfolded polypeptide or random coil after being translated from a sequence of mRNA into a linear chain of amino acids.

Protein aggregation

In molecular biology, protein aggregation is a phenomenon in which intrinsically-disordered or mis-folded proteins aggregate (i.e., accumulate and clump together) either intra- or extracellularly. Protein aggregates have been implicated in a wide variety of diseases known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease. After synthesis, proteins typically fold into a particular three-dimensional conformation that is the most thermodynamically favorable: their native state.

Tau protein

The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT (microtubule-associated protein tau). They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.

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