R01NS123649

Molecular, Cellular, and Behavioral Impact of the R203W PACS1 Syndrome Mutation - Project Summary

PACS1 syndrome is a recently identified neurodevelopmental disorder caused by a recurrent de novo missense mutation in PACS1 (p.Arg203Trp). Patients carrying this missense mutation share several developmental deficits, including intellectual disability, seizures, and autism. The mechanism by which PACS1R203W causes PACS1 syndrome is unknown, and no curative treatment is available.

PACS1 is a multifunctional sorting protein that facilitates retrograde trafficking from endosomes to the trans-Golgi network for the delivery of proteins to the primary cilium and for genome integrity. This multifunctionality depends on a small segment of PACS1 called the furin-binding region (FBR), which binds a broad range of client proteins and signaling molecules. The R203W mutation is located in the FBR, and our biophysical studies reveal a change in the FBR dynamics when the R203W substitution is present, suggesting the possibility of an altered interaction between PACS1 and one or more of its client proteins in PACS1 syndrome.

Our preliminary studies strongly suggest that PACS1R203W increases binding to the deacetylase HDAC6, profoundly disturbing membrane traffic and impairing neuron development. Consequently, PACS1R203W reduces acetylation of known HDAC6 substrates, including α-tubulin, disrupting centrosome positioning and leading to Golgi fragmentation and increased dendritic arborization in pyramidal neurons. This dendritic overbranching is coupled to reduced inhibitory currents in L2/3 cortical neurons, resulting in an increased excitatory:inhibitory (E:I) ratio, similar to that found in other neurodevelopmental disorders. This suggests that PACS1R203W severely affects neuronal function and behavior.

Our long-term goal is to understand how PACS1R203W causes disease and to use this information to develop effective therapies. The objective of this particular application is to determine how PACS1R203W and HDAC6 combine to dysregulate neuronal arborization and synaptic transmission. We hypothesize that the aberrant interaction between PACS1R203W and HDAC6 alters organelle positioning, which contributes to excessive dendrite arborization and dysregulated synaptic activity. Guided by strong preliminary data, we will test our hypothesis by pursuing three specific aims: 1) determine how the R203W mutation alters PACS1 structure and dynamics to influence client protein interactions, 2) determine how PACS1R203W and HDAC6 combine to dysregulate Golgi positioning and dendrite arborization, and 3) determine how PACS1R203W alters synaptic activity and behavior.

The approach is innovative because we will characterize, from the atomic structure to the whole organism, the mechanism by which the recurrent R203W substitution causes neuronal dysfunction. This research is significant because it may identify new targets and therapeutic approaches to treat this debilitating disorder.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

(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 THE NEUROSCIENCE WORKFORCE, 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]

Pittsburgh, Pennsylvania 152221808 United States

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

Amendment Since initial award the total obligations have increased 399% from $651,903 to $3,251,840.