Monday, May 12, 2025
5/12/2025
Assembling the Genetic Architecture of X-linked Dystonia Parkinsonism - ABSTRACT X-linked dystonia-parkinsonism (XDP) is a fully penetrant and lethal neurodegenerative disorder in which symptoms of dystonia overlap with degenerative parkinsonism, reflective of the gradual loss of striatal neurons as the disease progresses. XDP represents a unique Mendelian disorder that offers the opportunity to study dysfunction in the basal ganglia given the genetic, mechanistic, and phenotypic overlaps with other forms of dystonia, Parkinson’s disease, Huntington’s disease, and the tauopathies. Our initially funded program developed an innovative genome and transcriptome assembly approach, coupled with extensive neuronal modeling, to discover that an SVA insertion into intron 32 of the TAF1 gene was associated aberrant transcriptional signatures that included intron retention (IR) and alternative splicing (AS), as well as reduction of TAF1 expression in patient derived neural stem cells (NSCs) and induced neurons (iNs). This mutation was also associated with global changes in neurodevelopmental and inflammation pathways, consistent with the functions of TAF1 as a key transcriptional regulator. We surprisingly found that age-at-onset and disease expression were modified by a variable hexameric repeat within the SVA, and that CRISPR-excision of the SVA rescued all transcriptional aberrations in XDP, suggesting a path to amelioration. In this renewal, we will leverage strong new preliminary results that suggest: 1) antisense oligonucleotides (ASO) can alter TAF1 splicing in XDP; 2) all molecular signatures discovered in neuronal cell models are confirmed in postmortem brain tissue from XDP cases and are tissue-specific; 3) there is clear evidence of tau accumulation in XDP postmortem brain tissues. To pursue our foundational discoveries and new findings, we will conduct a series of studies across a highly complementary team of investigators to define the pathogenic mechanisms and possible targeted therapies for XDP. Aim 1 will apply ASO therapies to manipulate AS and IR in neuronal models and modulate TAF1 expression, then explore the perturbation and rescue of molecular signatures. Aim 2 will use a unique XDP brain bank to study the transcriptomic and proteopathic features of XDP in postmortem brains, where our preliminary data indicate that neuropathologic changes in XDP are consistent with a previously unrecognized tauopathy. We will systematically profile and quantify the burden of tau across multiple brain regions, as well as the biochemical and structural characteristics of pathologic tau in XDP. Using patient biosamples, we will also seek potential biomarkers of this pathology. Aim 3 will then integrate ASO/CRISPR targeting and tau dynamics with prior data that support a role for inflammation and iron-mediated toxicity in XDP. We will develop neuron:glial co-cultures, and characterize the responses of these cell types to tau, iron, and inflammatory stimuli. These interdisciplinary and interconnected aims will provide broad mechanistic and therapeutic insights into this unique Mendelian disorder with profound implications for more common neurodegenerative diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).