R01NS132330

Investigating the role of TMEM106B genetics and pathology in Alzheimer's disease, late and FTLD - project summary/abstract.

Filaments derived from transmembrane protein 106B (TMEM106B) were recently discovered to represent a novel pathological hallmark in a range of neurodegenerative disorders, including TDP-43 proteinopathies, synucleinopathies, and tauopathies.

Notably, TMEM106B genetic variants are linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), particularly cases with progranulin (GRN) and chromosome 9 open reading frame 72 (C9ORF72) mutations, and limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathologic change.

TMEM106B variants also associate with cognitive decline in patients with amyotrophic lateral sclerosis.

While several single nucleotide polymorphisms (SNPs) in TMEM106B have been identified and linked to disease risk, only one (RS3173615) introduces a coding change (p.T185S) and it is in high linkage disequilibrium with other risk SNPs.

To investigate the intriguing idea that RS3173615 could modulate disease risk through regulation of TMEM106B deposition, we developed an antibody against the TMEM106B filament core sequence.

Consistent with recent reports, we detected TMEM106B-positive filaments in the sarkosyl-insoluble fraction from FTLD-TDP and LATE patients.

Remarkably, we also observed increased accumulation of insoluble TMEM106B in FTLD-TDP patients homozygous for the RS3173615 risk allele (encoding threonine at residue 185 instead of serine).

Collectively, these findings support the hypothesis that TMEM106B aggregation explains the link between genetic variation at the TMEM106B locus and disease risk – and we suspect that it could also explain potential links between RS3173615, TDP-43 proteinopathy, and cognitive decline.

We also speculate that differences in TMEM106B accumulation contribute to clinical and pathologic heterogeneity in both FTLD and LATE.

Moreover, given that LATE is associated with greater hypometabolism on [18F] fluorodeoxyglucose PET (FDG-PET) in the frontal lobe, a region populated by TMEM106B fibrils, we predict that RS3173615 genotype will also associate with neuroimaging measures of neurodegeneration.

In this project, we will investigate the impact of RS3173615 genotype on TMEM106B aggregation and assess whether it associates with TDP-43 proteinopathy and clinical outcomes.

We will also explore the mechanism by which the RS3173615 coding variant affects TMEM106B fibril formation, as well as the potential functional consequences of TMEM106B genetic variation and fibril accumulation.

Our approach to the latter will be two-fold: as a candidate-based approach, we will determine whether TMEM106B genetic variants impact lysosomal function in neurons, and as an unbiased approach, we will use proteomic analyses to build protein-protein interaction and co-aggregation networks from the soluble and insoluble fractions of patient brains, focusing on differences observed in carriers of the T185 allele versus carriers of the S185 protective genotype.

Mayo Clinic Jacksonville (A Nonprofit Corporation)

(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]

Jacksonville, Florida 322241865 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)

Amendment Since initial award the total obligations have increased 194% from $1,097,060 to $3,221,644.