Research Impact
NEW - Article State of HSP Research:The Promise and the Reality by Allen Bernard
The Spastic Paraplegia Foundation is dedicated to advancing research and ultimately finding the cures for two closely related groups of neurodegenerative disorders termed Hereditary Spastic Paraplegia (HSP) and Primary Lateral Sclerosis (PLS). These conditions share the common pathologic feature of degeneration principally of the upper motor neurons.
Scientists have unraveled many of the riddles regarding the complicated biochemistry of these diseases. Many HSP genes have now been discovered as well as a gene for PLS. Animal models for these disorders have been developed. They will enable investigators to further uncover the biochemical processes that cause nerve degeneration and identify and test therapy targets.
An increased focus on our diseases is timely and critical. There is indeed reason to hope for treatments and therapies in coming years that will restore significant function to people affected by SPF diseases. And, uncovering more of these riddles may also lead to important findings for related conditions such as ALS, spinal cord injury and Alzheimer's Disease. Researchers say common threads link the many neurologic conditions that affect millions of people.
2011
 |
Paola Arlotta, Ph.D.
Assistant Professor of Stem Cell and Regenerative Biology, Harvard University
"Molecular mechanisms of corticospinal motor neuron dysfunction in HSP and PLS"
|
 |
Melissa M. Rolls, Ph.D.
Assistant professor, Biochemistry and Molecular Biology, Penn State University, University Park, PA
"Function of spastin in axon regeneration: a new role for the HSP protein Spastin"
|
 |
Xue-Jun Li, Ph.D.
Assistant Professor, Health Science Center, Department of Neuroscience, University of Connecticut, Farmington CT
"Elucidating the role of BMP signaling in HSP using patient-specific induced pluripotent stem cells"
|
 |
John K. Fink, M.D.
Professor, Department of Neurology, University of Michigan, Ann Arbor, MI,
"Natural history of primary lateral sclerosis and hereditary spastic paraplegia: establishing parameters for clinical trials"
|
|
Nichole Hein, Ph.D
Postdoctoral Fellow, Department of Neurology, University of Michigan, Ann Arbor, MI
"In vitro models of Primary Lateral Sclerosis and Hereditary Spastic Paraplegia"
|
2010
 |
Dong-Hui Chen, M.D., Ph.D.
Research Assistant Professor, Department of Neurology, University of Washington, Seattle, WA
"Genome-wide detection of mutations in all
genes to identify the cause of a new familial spastic paraplegia."
|
 |
Susan K. McConnell Ph.D.
Susan B. Ford Professor of Humanities and Sciences, Department of Biological Sciences, Stanford University, Stanford, CA
"Optimal transplantation strategies for the reconstruction of corticospinal
circuitry in HSP and PLS."
|
|
Robert D. Nicholls, D.Phil.
Director, Birth Defects Laboratories, and Division of Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA
"A Proposal for a Roadmap that Links Different Spastic Paraplegias."
|
 |
Teepu Siddique, M.D.
Les Turner ALS Foundation/ Herbert C. Wenske Professor, Davee Department of Neurology and Clinical Neurosciences and Department of Cell and Molecular Biology, Director, Division of Neuromuscular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
"NTE-induced Upper Motor Neuron Degeneration in Primary Lateral Sclerosis."
|
2009
 |
Hiroshi Mitsumoto, MD, D.Sc.
Wesley J. Howe Professor of Neurology, Director, Eleanor & Lou Gehrig MDA/ALS Center, The Neurological Institute, Columbia University College of Physicians and Surgeons, New York, NY
"Multicenter Prospective PLS Natural History Study"
|
 |
Elena Irene Rugarli, M.D.
University of Cologne, Germany.
"Exploring alternative functions of paraplegin, a protein involved in autosomal
recessive and sporadic HSP."
|
2008
|
|
Paola Arlotta, Ph.D.
Massachusetts General Hospital, Center For Regenerative Medicine, Boston, MA
"Directed Differentiation of Neural Progenitors and iPS Cells into Corticospinal
Motor Neurons"
|
 |
Janine Kirby, Ph.D.
Christopher John McDermott, Ph.D. Professor Pamela Shaw Academic Neurology Unit, The University of Sheffield Medical School, Sheffield, United Kingdom
"Elucidation of upper motor neuron vulnerability in Primary Lateral Sclerosis"
|
 |
Yasushi Kisanuki, M.D.
Department of Neurology, Ohio State University, Columbus, OH
"Paraplegia in HSP Rat: Analysis and treatment"
|
 |
Jeffrey Macklis, M.D. D.HST.
Paola Arlotta, Ph.D. Massachusetts General Hospital – Harvard Medical School Center for Nervous System Repair, Boston, MA
"Molecular-Genetic Controls over the Development, Connections, and Survival of Upper
Motor Neurons"
|
2007
 |
Peter W. Baas, Ph.D.
Department: Neurobiology and Anatomy, Drexel University, Philadelphia, PA
"Mechanistic Basis of SPG4-based Hereditary Spastic Paraplegia"
Challenged the prevailing "loss of function" theory for how mutant SPG4/ Spastin
causes HSP by showing that the defective protein expressed by this gene is actually
toxic to neurons. Other proteins can perform the cellular function not being performed
by defective Spastin protein. Published the results of his work in the February,
2008 issue of The Journal of Neuroscience, and the April, 2008 issue of the journal
Molecular Biology of the Cell.
|
 |
Bruce Horazdovsky, Ph.D.
Department of Biochemistry & Molecular Biology and The Mayo Clinic Cancer Center, Associate Dean, Mayo Clinic College of Medicine Rochester, MN
"Development of a cell culture system to analyze defects associated with Primary
Lateral Sclerosis"
Developed a differentiated and polarized human cell culture system to evaluate the
function of the protein Alsin in the normal and disease states. This step was necessary
to apply for a large NIH grant regarding the protein Alsin (mutations in the ALS2/
Alsin gene cause infantile onset PLS, HSP and ALS).
|
 |
Stephan Zuchner, M.D.
Director, Center for Human Molecular Genetics, Miami Institute for Human Genetics, Leonard M. Miller School of Medicine, Miami, FL
"Molecular and genetic analysis of the SPG31 gene REEP1"
|
2006
|
|
John K. Fink, M.D.
Professor, Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI,
"Developing treatment for childhood onset Hereditary Spastic Paraplegia (SPG3A HSP)"
|
|
|
Jeffrey Macklis, M.D. D.HST.
Paola Arlotta, Ph.D. Massachusetts General Hospital – Harvard Medical School Center for Nervous System Repair, Boston, MA,
"Molecular-genetic Controls over the Development, Connections, and Survival of Upper
Motor Neurons"
Drs. Macklis's and Arlotta's work for the SPF is ongoing. They are investigating
the molecular controls involved in the development, connectivity and survival of
motor neurons in the central nervous system.
|
 |
Nina Tang Sherwood, Ph.D.
IGSP Scholar and Assistant Research Professor of Biology, Duke University, Durhan, NC,
"Understanding the ameliorative effects of temperature in fruit fly models of AD-HSP"
Dr. Sherwood's work for the SPF is ongoing. Results have not been published or made
public.
|
 |
Kendal S. Broadie, Ph.D.
Professor of Neurobiology, Vanderbilt University, Nashville, TN
"Mechanistic Interactions among Hereditary Spastic Paraplegia Genes"
|
2005
|
|
Kendal S. Broadie, Ph.D.
Professor of Neurobiology, Vanderbilt University, Nashville, TN
"Mechanistic Interactions among Hereditary Spastic Paraplegia genes"
Discovered that in flies, Spastin and Atlastin proteins act together in microtubule
dynamics regulation to control neuron structure and function.
|
|
Blair R. Leavitt, Ph.D. & Michael R. Hayden, M.D., Ph.D.
Department of Medical Genetics, The Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada,
"Revealing the Mechanisms underlying ALS2, a form of hereditary spastic paraplegia,
using ALS2 -/- mice"
Developed mice without ALS2 genes (eliminating the production of any Alsin protein
in these animals) and performed a thorough characterization of these mice. The mice
showed loss in motor performance of relatively late onset in their life-span (compared
to human patients with mutations in their ALS2 genes), and much milder in degree.
Also discovered a disturbance of intracellular transport, consistent with the known
biochemical functions of Alsin. Findings were presented at the Society for Neuroscience
meeting in 2006. Also published findings in the respected journal The Proceedings
of the National Academy of Science.
|
 |
Peter Hedera, M.D.
Assistant Professor, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN,
"Invertebrate model of Hereditary Spastic Paraplegia"
Created a line of C. elegans (a microscopic worm) with HSP caused by mutations in
their SGG6/ NIPA1 gene, and another line of these worms with HSP caused by knocking
out their SPG2A/ Atlastin gene. Determined that HSP caused by mutations in the SPG6/
NIPA1 gene is associated with accumulation of misfolded NIPA1 protein, which triggers
neuronal degeneration and programmed cell death. In a line of C. elegans with mutant
SPG6/ NIPA1 genes and a mutation in another gene that causes the worms to be resistant
to programmed cell death, observed that the disease course was slower and less severe.
Published findings in the December, 2008 issue of the Journal of Neuroscience.
|
|
Brett Peter Lauring, M.D., Ph.D.
Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY,
"Analysis of Spastin and Atlastin in the cell biology of neurons"
Confirmed that loss of Spastin function results in prematurely terminating motor
axons in C. elegans. Developed a line of C. elegans with mutated human SPG4/ Spastin
genes. Published the results of his work in the July, 2006 issue of the The Proceedings
of the National Academy of Science, the March, 2007 issue of the Journal of Cell
Biology, the July, 2007 issue of the Journal of Cell Science, and the December,
2007 issue of the journal Traffic.
|
|
|
Jeffrey Macklis, M.D., D.HST
Director, Massachusetts General Hospital – Harvard Medical School Center for Nervous System Repair, Boston, MA,
"Molecular-genetic Controls over the Development, Connections, and Survival of Upper
Motor Neurons"
Dr. Macklis's work for the SPF is ongoing. He is investigating the molecular controls
involved in the development, connectivity and survival of motor neurons in the central
nervous system. Has published eight medical journal articles on his groundbreaking
work to date.
|
2004
  |
Vincent T. Cunliffe, Ph.D. & Jonathan D. Wood, Ph.D.
Centre for Developmental Genetics and Department of Neurology, University of Sheffield, Sheffield, United Kingdom
"Modelling the neurodegenerative processes caused by mutation of the spg4 gene in
zebrafish and development of strategies for pharmacological intervention"
Discovered a crucial role for Spastin (defective Spastin causes the most common
type of adult onset HSP) in promoting axon outgrowth in the zebrafish embryo. The
discovery was published in the high profile journal Human Molecular Genetics, and
the journal also included an image from the paper on the cover of the issue in which
the article appeared, further enhancing the visibility of the research.
|
|
|
Teepu Siddique, M.D.
Director, Neuromuscular Disorders Program, The Feinberg School of Medicine, Northwestern University, Chicago, IL
"The PLS Registry"
Expanded the PLS Registry to include blood specimens from 214 PLS patients, including
118 sets of patients with an unaffected sibling, and 33 sets with a patient and
both parents.
|
2003
|
|
John K. Fink, M.D.
Professor, Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI
"Primary Lateral Sclerosis: molecular genetic analysis"
The project sought to determine if one of the binding partners of the protein Alsin
(defective Alsin causes juvenile onset PLS, ALS and HSP) is Atlastin (defective
Atlastin causes juvenile onset HSP). Although several proteins were discovered that
interacted with Atlastin in a yeast model, Alsin was not one of them.
|
 |
Douglas Marchuk, Ph.D.
Department of Molecular Genetics & Microbiology, Duke University, Durham, NC
"A Mouse Model for Hereditary Spastic Paraplegia"
Developed a line of mice into which the mutated, human gene KIF5A was incorporated.
(Mutated KIF5A causes HSP.) These mice developed several symptoms consistent with
human HSP. These mice were then cross-bred with another line of mice that had been
developed by Dr. Larry Goldstein at the University of California, San Diego that
had only one copy of the KIF5A gene. This was done to attempt to develop mice that
developed more severe HSP-like symptoms and at an earlier age. By the end of the
period of grant funding, those mice were too young to have developed symptoms.
|
