Abstract

The purpose of the Neurogenetics Branch is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. Particular areas of research interest include the polyglutamine expansion diseases (Huntington's disease, Kennedy's disease, and spinocerebellar ataxia), spinal muscular atrophy, Charcot-Marie-Tooth disease, muscular dystrophy, hereditary motor neuron disease, and Friedreich's ataxia. The disease mechanisms are studied in cell culture and other model systems. A genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. A trial of idebenone treatment in Friedreich's ataxia was recently completed, and a trial of dutasteride treatment for Kennedy's disease is in progress. Further therapeutic trials are anticipated. Specific research accomplishments in the past year include the following: (1) We further characterized the mechanism of neuronal death in cell culture and Drosophila models of polyglutamine disease, investigating the role of profilin and the beneficial effects of IGF-1. (2) We further characterized the biochemical effects and clinical and pathological manifestations of a mutation in the transport protein dynactin in an autosomal dominant form of motor neuron disease. (3) We further characterized the manifestations of motor neuronopathy due to mutations in glycyl-tRNA synthetase. (4) We reported further studies of X-linked Charcot-Marie-Tooth disease in transgenic mice. (5) We further characterized the effects of histone acetylation and histone deacetylase inhibitors on the expression of SMN, the gene that is mutated in spinal muscular atrophy, and we demonstrated a therapeutic response in a mouse model of the disease. (6) We completed a phase 2 study of idebenone treatment in Friedreich's ataxia comparing high dose, low dose, and placebo treatment. (7) We started a placebo-controled phase 2 study of dutasteride treatment in Kennedy's disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002974-08
Application #
7324552
Study Section
(NGB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2006
Total Cost
Indirect Cost

  Institution

Name
National Institute of Neurological Disorders and Stroke
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Traore, M; Landoure, G; Motley, W et al. (2009) Novel mutation in the NHLRC1 gene in a Malian family with a severe phenotype of Lafora disease. Neurogenetics 10:319-23
Pierson, T M; Zimmerman, R A; Tennekoon, G I et al. (2008) Mega-corpus callosum, polymicrogyria, and psychomotor retardation: confirmation of a syndromic entity. Neuropediatrics 39:123-7
Mochel, Fanny; Knight, Melanie A; Tong, Wing-Hang et al. (2008) Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. Am J Hum Genet 82:652-60
Brewer, Megan; Changi, Febriani; Antonellis, Anthony et al. (2008) Evidence of a founder haplotype refines the X-linked Charcot-Marie-Tooth (CMTX3) locus to a 2.5 Mb region. Neurogenetics 9:191-5
van de Leemput, Joyce; Chandran, Jayanth; Knight, Melanie A et al. (2007) Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet 3:e108
Sumner, C J; Kolb, S J; Harmison, G G et al. (2006) SMN mRNA and protein levels in peripheral blood: biomarkers for SMA clinical trials. Neurology 66:1067-73
Lorenzo, D N; Forrest, S M; Ikeda, Y et al. (2006) Spinocerebellar ataxia type 20 is genetically distinct from spinocerebellar ataxia type 5. Neurology 67:2084-5
Sumner, Charlotte J (2006) Therapeutics development for spinal muscular atrophy. NeuroRx 3:235-45
Kolb, Stephen J; Gubitz, Amelie K; Olszewski Jr, Robert F et al. (2006) A novel cell immunoassay to measure survival of motor neurons protein in blood cells. BMC Neurol 6:6
Jeng, Linda Jo Bone; Balice-Gordon, Rita J; Messing, Albee et al. (2006) The effects of a dominant connexin32 mutant in myelinating Schwann cells. Mol Cell Neurosci 32:283-98

Showing the most recent 10 out of 72 publications