Motor neuron diseases (MNDs) are neurodegenerative disorders that cause muscle weakness and often respiratory failure and death. Rapid progress in the molecular genetics of MNDs has revealed at least 22 distinct genes that are expressed in all cells and yet result exclusively in motor neuron (MN) loss when mutated. The small heat shock protein B1 (HSPB1, formerly HSP27) is mutated in patients with hereditary motor neuropathy (HMN). HSPB1 is unique among MND-causing genes in that overexpression of the wild type HSPB1 is known to be neuroprotective in MNs whereas mutations are toxic to MNs. The primary goal of this proposal is to determine the molecular function of HSPB1 that is relevant to motor neuron survival. To do this, we have developed a mouse model of motor neuropathy expresing the most common HSPB1 mutation (R136W) in neurons. We find that HSPB1 mutant mice display a phenotype of mild weakness that mimics HMN. We propose to develop a second line of mice expressing mutant HSPB1 in all cells so that we may distinguish between MN and non-MN contributions to MN injury. The role of non-neuronal cells in the progression of MND is emerging as an important concept and genes expressed by microglia in particular may be important targets in reducing MN loss in MNDs. We hypothesize that animals expressing HSPB1(R136W) in all cells will have a phenotype that is more severe than animals expressing HSPB1(R136W) exclusively in neurons. HSPB1 is required for a specific mRNA decay pathway caled AU-rich element (ARE)-dependent mRNA decay. AU-rich element mRNA decay is a critical mechanism in all cells to control the expression of a select group of mRNAs. Our preliminary data demonstrate that HSPB1(R136W) is defective in this RNA decay pathway, which raises the possibility that ARE-containing mRNAs (normally degraded via this pathway) may play a role in MN pathology. Many of these genes encode proteins such as interferons and inflammatory cytokines which have protective functions during injury and infections, but can be damaging when upregulated. We hypothesize that mRNA levels of ARE-containing mRNAs will be elevated in MNs and microglia expressing mutant HSPB1 compared to wild type HSPB1. To test this, we will directly measure ARE-containing mRNAs in MNs and microglia in mice. The development of these animals and the identification of the molecular function of HSPB1 that is important for MN survival will lead to new therapeutic targets and treatments for patients with HMN and has great potential to advance our understanding of and provide novel treatment strategies for all MNDs.

Public Health Relevance

The HSPB1 protein plays a critical role in an important RNA decay pathway and is neuroprotective in motor neurons. The proposed studies of HSPB1 function are highly likely to provide novel insights into normal motor neuron function and to the pathogenesis of motor neuron diseases. Ultimately, this project will lead to the identification of novel targets for the treatment of this devastating class of nervous system disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Schools of Medicine
United States
Zip Code
Heilman, Patrick L; Song, SungWon; Miranda, Carlos J et al. (2017) HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons. Exp Neurol 297:101-109
Iyadurai, Stanley; Arnold, W David; Kissel, John T et al. (2017) Variable phenotypic expression and onset in MYH14 distal hereditary motor neuropathy phenotype in a large, multigenerational North American family. Muscle Nerve 56:341-345
Kolb, Stephen J; Coffey, Christopher S; Yankey, Jon W et al. (2016) Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol 3:132-45
Duque, Sandra I; Arnold, W David; Odermatt, Philipp et al. (2015) A large animal model of spinal muscular atrophy and correction of phenotype. Ann Neurol 77:399-414
Arnold, W David; Sheth, Kajri A; Wier, Christopher G et al. (2015) Electrophysiological Motor Unit Number Estimation (MUNE) Measuring Compound Muscle Action Potential (CMAP) in Mouse Hindlimb Muscles. J Vis Exp :
Renusch, Samantha R; Harshman, Sean; Pi, Hongyang et al. (2015) Spinal Muscular Atrophy Biomarker Measurements from Blood Samples in a Clinical Trial of Valproic Acid in Ambulatory Adults. J Neuromuscul Dis 2:119-130
Kolb, Stephen J; Kissel, John T (2015) Spinal Muscular Atrophy. Neurol Clin 33:831-46
Meyer, Kathrin; Ferraiuolo, Laura; Miranda, Carlos J et al. (2014) Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A 111:829-32
Arnold, W David; Porensky, Paul N; McGovern, Vicki L et al. (2014) Electrophysiological Biomarkers in Spinal Muscular Atrophy: Preclinical Proof of Concept. Ann Clin Transl Neurol 1:34-44
Kolb, Stephen J (2013) NeuroNEXT SMA biomarkers study. Ann Neurol 74:A8

Showing the most recent 10 out of 15 publications