CERM Lecture 1A

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Information about CERM Lecture 1A
Education

Published on January 4, 2008

Author: Crystal

Source: authorstream.com

Slide1:  Lecture 1 • SOD1-ALS link: • Gain of function mechanism • Protein aggregation vs. oxidative damage • Chemistry of superoxide and other ROS Lecture 2 • ALS: Clinical aspects • SODs and SOD mechanisms Lecture 3 • Model studies in cell culture and ALS Tg mice and rats • WT and mutant SOD1 structures Lecture 4 • Protein aggregation and disease • Oxidative stress in ALS? Lecture 5 • Biophysical properties of WT and mutant SOD1s Molecular Mechanisms of CuZnSOD-Linked ALS Slide2:  Lecture 1 • SOD1-ALS link: • Gain of function mechanism • Protein aggregation vs. oxidative damage • Chemistry of superoxide and other ROS Lecture 2 • ALS: Clinical aspects • SODs and SOD mechanisms Lecture 3 • Model studies in cell culture and ALS Tg mice and rats • WT and mutant SOD1 structures Lecture 4 • Protein aggregation and disease • Oxidative stress in ALS? Lecture 5 • Biophysical properties of WT and mutant SOD1s Molecular Mechanisms of CuZnSOD-Linked ALS Slide3:  Amyotrophic Lateral Sclerosis (ALS) or Motor Neuron Disease “Lou Gehrig’s Disease” in USA, named for famous baseball player Slide5:  Death of motor neurons causes paralysis of muscles in ALS ALS spinal cord ALS causes denervation and atrophy of muscle due to death of spinal motor neurons:  ALS causes denervation and atrophy of muscle due to death of spinal motor neurons Slide7:  Motor Neurons Affected in ALS Upper motor neurons (MN) are in the top part of the brain. Upper MN affect all of the body’s voluntary muscles by sending neurotransmitters to the lower motor neurons. Upper MN regulate the activity of the lower motor neurons, which in turn send neurotransmitters to the muscles. Lower motor neurons are in the brainstem (almost at the spinal cord) and the spinal cord. Lower MN in the brainstem control voluntary muscles in the face, mouth, throat and tongue. Lower MN in the spinal cord control all the other voluntary muscles of the body, such as those in the limbs, trunk, head and neck, as well as the respiratory diaphragm and other muscles used in breathing. Slide8:  Rowland and Schneider, NEJM 322:1688 (2001) Loss of brain motor neurons (UMN)  spasticity and hyperreflexia Loss of spinal motor neurons (LMN)  skeletal muscle denervation and atrophy Non-motor systems are typically spared Focal onset with local spread of signs Slide9:  Loss of lower motor neurons results in muscle weakness, atrophy (loss of bulk), cramping and twitching. Loss of upper motor neurons results in muscle weakness, stiffness, slowness of movement, and tightness, or spasticity. Slide10:  Norris et al. Neurol Sci 118 (1):51 (1993) Peak incidence of sporadic ALS is between ages 55 – 75, with a slight male predominance Half of all people affected with ALS live less than 3 years after diagnosis. Twenty percent live 5 years or more. Lifetime risk is 1 in 2000. No remissions, no cures, no effective drug treatment Lou Gehrig’s Batting Average Declined Sharply During the 1938 Season :  Lou Gehrig’s Batting Average Declined Sharply During the 1938 Season Slide12:  Not Inherited (Sporadic ALS) ~90% Many genes, most are not identified mutations in CuZnSOD Seemingly random, no known cause CuZnSOD-associated FALS is ~ 2% of total cases of ALS Two types of ALS: Inherited (Familial ALS) ~10% Genetics of ALS:  Genetics of ALS Classification Inheritance Locus Gene Protein ALS1 AD/AR 21q22 SOD1 Cu/Zn SOD ALS2 AR 2q33-34 ALSin Alsin *ALS3 AD Unknown (70-80% of fALS) ALS4/dHMN AD 9q34 SETX Senataxin ALS5 AR 15q12-21 ALS6 AD 18q21 FTD-P AD 17q TAU (13-40%) Tau ALS-FTD AD 9q21-22 Copper-Zinc Superoxide Dismutase (CuZnSOD):  Copper-Zinc Superoxide Dismutase (CuZnSOD) 32,000 Da molecular weight dimeric protein “Erythrocuprein” 1930’s SOD activity Fridovich & McCord 1969 Link to ALS 1993 Found in cytoplasm, mitochondrial IMS, nucleus, peroxisomes Metal Binding Sites and SOD Mechanism:  Metal Binding Sites and SOD Mechanism Metal binding properties of the two sites are coupled Enzymatic reaction: Active Site Channel and Superoxide Specificity:  Active Site Channel and Superoxide Specificity Slide17:  Location of Known ALS Mutations SOD1 monomer Slide18:  Location of Known ALS Mutations Each black sphere represents a different amino acid where a mutation is known to cause ALS ALS-Mutant SOD1 is Toxic to Motor Neurons:  “Loss of Function” Hypothesis: Does low SOD activity cause ALS? No Mice with no SOD1 protein do not develop ALS. ALS-Mutant SOD1 is Toxic to Motor Neurons G37R SOD1 mouse “Gain of Function” Hypothesis: Is ALS-mutant CuZnSOD toxic? Yes Mice with ALS mutant human SOD1 plus normal mouse SOD1 do develop ALS. The ALS phenotype may vary with different SOD1 FALS mutations and genetic backgrounds:  The ALS phenotype may vary with different SOD1 FALS mutations and genetic backgrounds A4V Rapidly progressive, short survival (~ 1 year) Minimal involvement of upper motor neurons G37R Long survival Both upper and lower motor neurons involved D90A Only homozygotes affected in northern Sweden and Finland Atypical onset (sensory prodrome for months to years) Long survival (>15 years), no pathology available yet 28 families thought to arise from one founder mutation G93S May entail sensory and autonomic disturbance I113T Course can be rapidly progressive, but variable Massive neurofilament accumulations observed in MN Slide21:  A4V mutation The substitution of Alanine 4 by Valine (the A4V mutation) is one of the most common mutations that cause CuZnSOD-associated ALS. Mechanisms Suggested for Toxic Gain of Function of ALS-Mutant CuZnSOD:  Mechanisms Suggested for Toxic Gain of Function of ALS-Mutant CuZnSOD New chemical (pro-oxidant) reactivity for SOD1 damages cell components or SOD protein itself 2. Formation of CuZnSOD oligomers, aggregates, or co-aggregates with other unknown components Lewy Body-like Hyaline Inclusions in FALS:  Lewy Body-like Hyaline Inclusions in FALS Originally described in patients with FALS that involved the posterior columns and spinocerebellar tracts Hirano et al. Arch Neurol (1967) 16, 232-43 7-20 µM diameter Contain ubiquitin, CuZnSOD, and neurofilament proteins Abundant in many of the ALS CuZnSOD transgenic mice Ubiquitin-positive inclusions Inclusions containing precipitated, aggregated proteins, including CuZnSOD Mechanisms Suggested for Toxic Gain of Function of ALS-Mutant CuZnSOD:  Mechanisms Suggested for Toxic Gain of Function of ALS-Mutant CuZnSOD New chemical (pro-oxidant) reactivity for SOD1 damages cell components or SOD protein itself 2. Formation of CuZnSOD oligomers, aggregates, or co-aggregates with other unknown components Proposed Mechanisms of Mutant SOD1 Toxic Chemistry:  Proposed Mechanisms of Mutant SOD1 Toxic Chemistry Use of Aberrant Substrates Copper ions required Cleveland and Rothstein, Nature Rev Neurosci 2:806-19 (2001) EPR of Whole Yeast Treated with POBN and H2O2:  EPR of Whole Yeast Treated with POBN and H2O2 Important Questions:  Important Questions Why is mutant SOD1 toxic to motor neurons and why do the different mutant proteins give different symptoms and different survival times? How might aberrant biophysical properties of mutant SOD1 (e.g., misfolding, decreased stability, altered metal binding, or abnormal interactions) contribute to neurotoxic mechanisms in ALS? Do the different SOD1 mutant proteins all cause the disease by the same mechanism? Slide30:  Location of Known ALS Mutations SOD1 monomer Slide31:  Survival times for SOD1 mutations G37R, G41D, H46R*, and E100K >17 years G93C ~10 years E100G and G85R* ~5-6 years L38V, H43R, and G93A ~1-3 years A4V ~1 year H48Q* and S134N* may have very short survival times, but the numbers of patients with these mutations are too small to be certain. *Metal binding region mutants The explanation remains a frustrating puzzle… and a challenge. Slide32:  Lecture 1 • SOD1-ALS link: • Gain of function mechanism • Protein aggregation vs. oxidative damage • Chemistry of superoxide and other ROS Lecture 2 • ALS: Clinical aspects • SODs and SOD mechanisms Lecture 3 • Model studies in cell culture and ALS Tg mice and rats • WT and mutant SOD1 structures Lecture 4 • Protein aggregation and disease • Oxidative stress in ALS? Lecture 5 • Biophysical properties of WT and mutant SOD1s Molecular Mechanisms of CuZnSOD-Linked ALS Models of Mutant SOD1 Toxicity:  Models of Mutant SOD1 Toxicity Cleveland and Rothstein, Nature Rev Neurosci 2:806-19 (2001) Slide34:  Lecture 1 • SOD1-ALS link: • Gain of function mechanism • Protein aggregation vs. oxidative damage • Chemistry of superoxide and other ROS Lecture 2 • ALS: Clinical aspects • SODs and SOD mechanisms Lecture 3 • Model studies in cell culture and ALS Tg mice and rats • WT and mutant SOD1 structures Lecture 4 • Protein aggregation and disease • Oxidative stress in ALS? Lecture 5 • Biophysical properties of WT and mutant SOD1s Molecular Mechanisms of CuZnSOD-Linked ALS

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