R37NS112503

Mechanism of Stathmin-2-dependent axon maintenance, regeneration, and function - abnormal nuclear depletion and cytoplasmic accumulation of the RNA-binding protein TDP-43, is reported in a large spectrum of age-dependent neurodegenerative conditions referred as TDP-43 proteinopathies that include almost all instances of amyotrophic lateral sclerosis (ALS), >40% of frontal temporal dementia (FTD), up to 50% of Alzheimer's disease (AD) and elderly patients with an AD-like dementia named limbic-predominant age-related TDP-43 encephalopathy (LATE).

TDP-43 is an essential protein involved in fundamental processing activities in the thousands of RNA transcripts to which it binds, regulating expression, splicing, and transport.

We discovered that the human mRNA most affected by reduced TDP-43 function encodes the neuron-specific protein Stathmin-2 (encoded by the STMN2 gene) whose loss is now recognized as a pathological hallmark in all patients with TDP-43 proteinopathy.

TDP-43 is required to prevent the inclusion of a cryptic exon within the first intron of STMN2 pre-mRNA.

We determined that TDP-43 binding sterically blocks STMN2 pre-mRNA misprocessing, preventing its cryptic splicing and truncation.

We also demonstrated that antisense oligonucleotides (ASOs) can restore normal Stathmin-2 levels in the nervous system upon TDP-43 dysfunction.

We recently showed that chronic focal loss of Stathmin-2 from the mammalian adult lumbar spinal cord is sufficient to drive the earliest clinical signs of ALS, including progressive muscle denervation and neurofilament-dependent axonal collapse.

Stathmin-2 has been proposed to regulate microtubule dynamics through a Stathmin-like domain which binds two A/B-tubulin heterodimers in a phosphorylation-dependent manner.

In cultured human neurons, Stathmin-2 is required for regeneration after an initial injury by axotomy, with elevated protein levels in regenerating neurons, axons, and growth cones.

Here we seek continuing support for a comprehensive investigation into the role of Stathmin-2 in axonal maintenance and regeneration using human induced pluripotent stem cell-derived neurons and mouse models.

We will determine the mechanism(s) through which Stathmin-2 (and its partner proteins that we will identify) mediate maintenance of neuromuscular junctions, axonal structure, and regeneration in the adult nervous system.

We will assess whether tubulin and membrane binding capabilities of Stathmin-2 are necessary for axonal functionality in human neurons, determine the impact of sustained suppression of Stathmin-2 on axonal structure and synaptic function within the brain, and establish the feasibility of Stathmin-2 gene replacement strategies.

San Diego University Of California

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

La Jolla, California 92093 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have decreased 12% from $3,495,400 to $3,072,075.