Grants

Linking TDP-43 pathology to synaptic (dys)function in ALS and FTD

This project aims to mechanistically resolve a critical knowledge gap regarding the functional impact of pathological aggregation of TDP-43 protein on the structure and function of synapses. This project will provide greater insight into how one of the key molecules involved in ALS and frontotemporal dementia (FTD) TDP-43 leads to a breakdown of cellular communication within the brain, thus yielding mechanistic insights that cut across multiple neurodegenerative diseases.

VAPB and membrane contact sites in amyotrophic lateral sclerosis (ALS) pathogenesis

This project aims to employ innovative technologies to better resolve the function and composition of cellular components that serve as a convergence point of pathogenic pathways involved in familial and sporadic ALS. This project could uncover a molecular pathway that unifies several subtypes of ALS under one molecular process, transforming how science thinks about ALS and discovering a compelling therapeutic target at the same time.

Understanding ALS mechanisms in a novel human cellular model of the cortico-motor pathway

This project aims to develop cutting-edge 3D cellular models that recapitulate the connection between the brain, spinal cord, and muscles of ALS patients. The team will use these novel models of ALS to compare the cellular composition, gene expression profiles, and genetic susceptibility of ALS-affected and unaffected cellular networks. Overall, these studies will generate a new ALS model using human cells†that could be transformative for studying†mechanisms underlying ALS and developing novel therapies.

Decoding the role of microglia in motor neuron selective vulnerability in Amyotrophic Lateral Sclerosis

This project aims to use state-of-the-art approaches for examining gene expression profiles and cellular connections to uncover the mechanisms underlying the differential vulnerability of different populations of motor neurons to degeneration in ALS. These studies will generate a valuable data set that other researchers can learn from and interrogate, promote further understanding of the role of microglia in preserving motor neuron health, and unveil novel therapeutic strategies.

Translational Neuroscience Initiative for Neurodegenerative Diseases

This project focuses on a Translational Neuroscience Initiative for Neurodegenerative Diseases. At the Innovative Genomics Institute, the research team uses medical records, laboratory models, and tissue collected from patients at autopsy to understand why neurons are vulnerable or resistant to degeneration.

Developing a Platform Trial for Frontotemporal Dementia

This study expands the work that GENFI (Genetic Frontotemporal dementia Initiative) has done to develop biomarkers into setting up a platform trial. A platform trial is a newer clinical trial structure that allows multiple therapies to be tested at the same time, reducing the cost and number of people required to adequately test a group of therapies.

Defining oligonucleotide therapeutics that reverse TDP-43 proteinopathy

This project aims to optimize the potential short RNAs that could reverse malfunctioning in some proteins (TDP-43) implicated in FTD. These short RNAs could provide an alternative treatment option that addresses malfunctioning TDP-43 without damaging its essential function, thus overcoming limitations of currently FDA-approved therapeutics.

Determining the impact of TMEM106b fibrils on FTLD pathogenesis

This study aims to better understand how certain genetic variants create vulnerabilities for the disease. It will elucidate how a genetic variant (TMEM106b-T185S) and its resulting protein (TMEM106b) confer an increased risk of FTD. The research team seeks to characterize how protein fibrils, formed when proteins misfold and aggregate, affect neurons and contribute to disease.

ON-FIRE: Open Network for Frontotemporal dementia Inflammation Research

This grant supports the ON-FIRE: Open Network for Frontotemporal Dementia Inflammation Research consortium. This consortium consists of 22+ locations that collect data from 300+ patients. This research team seeks to examine biomarkers in the blood to identify inflammation fingerprints, linking patterns of neuroinflammation with symptoms and progression in FTD.

Cryptic Exon Biomarker Discovery using Spatial Transcriptomics

This project aims to better understand certain forms of sporadic FTD, specifically those in which the TDP-43 protein malfunctions. The research seeks to answer questions about where in the brain those malfunctioning proteins are found and in what types of neurons, thus optimizing the detection of TDP-43 and resulting in better biomarkers for the disease.

Structural insight into TDP43 aggregation and lysosomal dysfunction in frontotemporal dementia (FTD)

This project will provide high-resolution insight into the structures of the irregular proteins (TDP-43) to better understand how these proteins malfunction in the brain to cause FTD. The results of this work could eventually inform imaging studies for detecting TDP-43 protein malformation.

TRIM11 as a therapeutic agent for sporadic FTD

This project develops a gene therapy approach to treat frontotemporal dementia (FTD) by using engineered viruses to deliver TRIM11, a protein that can clear toxic tau accumulations from brain cells. The key innovation is creating a system where TRIM11 production activates when toxic tau is present and switches off when the cell returns to normal, potentially making gene therapy safer and more precise for treating neurodegenerative diseases.

SPARC’s work with several of our partners includes implementing grant programs that fund biomedical research.