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Arthur Horwich, MD

Professor Emeritus of Genetics
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About

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Professor Emeritus of Genetics

Biography

Horwich received undergraduate and M.D. degrees from Brown University, trained in Pediatrics at Yale, was then a postdoctoral fellow first at Salk Institute in the Tumor Virology Laboratory, and then in Genetics at Yale, then joined the Yale faculty. His work was initially involved with protein import into mitochondria and resulted in discovery of a "folding machine" inside mitochondria, Hsp60. He has used genetic, biochemical, and biophysical tools to study the mechanism of action of these ring shaped so-called chaperonin machines that provide essential assistance to protein folding in many cellular compartments. More recently he has focused on neurodegenerative disease, modeling mutant SOD1-linked ALS in mice transgenic for a mutant SOD1 fused with a YFP reporter. In the transgenic mutant strain, the mutant SOD1 misfolds and lodges the fusion protein in YFP fluorescent aggregates, visible in motor neurons by 2-3 months of age. These neurons are removed by microglial cells, associated with loss of ~50% of motor neurons. By 6-7 months of age the mice exhibit lower extremity paralysis, associated with loss of ~50% of the remaining motor neurons. By contrast, a wtSOD1-YFP transgenic strain with the same amount of total SOD1-YFP protein in spinal cord remains asymptomatic even after two years, and the spinal cord remains free of aggregates. An early study showed that overexpression of the molecular chaperone Hsp110, known to be part of a chaperone disaggregase, improved survival of the SOD1-YFP mice. Additional genetic modifiers are being tested.

Appointments

Education & Training

Intern and Resident
Yale School of Medicine (1978)
MD
Brown University (1975)

Board Certifications

  • Genetics

    Certification Organization
    AB of Medical Genetics
    Original Certification Date
    1984
  • Pediatrics

    Certification Organization
    AB of Pediatrics
    Original Certification Date
    1982

Research

Overview

Studies of the past decades have shown that many diseases of neurodegeneration are associated with protein misfolding and aggregation of specific proteins in particular neurons or glia, and we have been studying one such mechanism of degeneration. We have focused on misfolding/aggregation caused by mutant forms of the anti-oxidant cytosolic enzyme SOD1 (superoxide dismutase), which produces dominant-inherited ALS, with progressive paralyzing motor neuron dysfunction. We are using mice overexpressing mutant G85R SOD1-YFP, containing a mutant version of SOD1 unable to reach the native state, studying the transgenic animals with a variety of approaches to investigate how the mutant SOD1 produces motor dysfunction.

We have identified that there is a progression of misbehavior of mutant SOD1 protein itself in the spinal cord motor neurons of transgenic animals. Initially it is soluble and associated to a significant extent with the abundant cytosolic chaperone Hsc70 (by contrast to the wild-type protein, which does not form such association, presumably because it occupies the native homodimeric state). Subsequently, the mutant SOD1 proteiin begins to form both soluble oligomers (observable by gel filtration chromatography) and insoluble aggregates, and at this point an additional molecular chaperone, Hsp110, becomes associated with the soluble aggregates. A portion of the aggregates becomes insoluble and forms large structures in the cytosol of motor neurons. These cells become surrounded by microglia and appear to be subsequently removed. Associated with such loss, the affected animal initially exhibits mild lower extremity symptoms (weakness or pulling in when held by the tail at ~ 3 months of age), which progresses over the next 3-4 months to paralysis, usually commencing in the lower extremities.

We have used laser capture microdissection of motor neurons and RNA-seq from animals at mid-course to inspect for changes in transcriptional expression, but find only a small number of differences relative to the motor neurons from wild-type SOD1-YFP mice. Notably, there is no classical heat shock response beyond induction of Hsp110 and no ER unfolded protein response, but there are effects on several calcium binding proteins. We surmised that most of the toxicity of mutant SOD1 is exerted post-translationally. In collaboration with David McCormick’s group we carred out electrophysiologic measurements of motor neurons by patch clamping them in spinal cord of wild-type and mutant SOD1 mice in novel rapidly prepared slice preparations. This identified that the fast-firing motor neurons, which innervate fast twitch muscle, are the first to be lost. This observation was confirmed by studying wild-type or mutant mice running on a wheel while simultaneously monitoring single motor neurons in the ventral horn of the spinal cord by field potential measurements and the firing of corresponding lower extremity muscles. Most recently we have been screening a number of candidate genes for prolongation of the survival of the mutant ALS mice.

Medical Subject Headings (MeSH)

Amyotrophic Lateral Sclerosis; Genetics; Motor Neurons; Neurodegenerative Diseases; Neurosciences; Pediatrics; Protein Folding; Superoxide Dismutase

Research at a Glance

Yale Co-Authors

Frequent collaborators of Arthur Horwich's published research.

Publications

2021

2020

2019

2017

2016

2015

2014

2012

2011

Academic Achievements & Community Involvement

  • honor

    American Academy of Arts and Sciences

  • honor

    Breakthrough Prize in Life Sciences 2020

  • honor

    Dr. Paul Janssen Award for Biomedical Research

  • honor

    Paul Ehrlich and Ludwig Darmstaedter Prize

  • honor

    E.B. Wilson Medal of American Society for Cell Biology

Get In Touch

Contacts

Academic Office Number
Office Fax Number

Locations

  • Boyer Center for Molecular Medicine

    Academic Office

    295 Congress Avenue, Ste Suite 145/154

    New Haven, CT 06510

    General Information

    203.737.4431