Biology subjects

Dauer, W. T.

Publications and source records attributed to Dauer, W. T..

7 recordsLinked to original sources

bioRxiv2026

Striatal cholinergic interneuron pathology and muscarinic signaling independently shape motor dysfunction in a DYT-TOR1A dystonia model

Antimuscarinic drugs are among the most effective pharmacological treatments for dystonia, yet the neural substrates underlying their therapeutic effects remain poorly understood. Striatal cholinergic interneurons (ChI) are strongly implicated in dystonia pathophysiology. In a symptomatic mouse model of DYT-TOR1A dystonia, torsinA loss from all striatal neurons causes selective ChI degeneration during juvenile maturation; surviving ChI exhibit persistent morphological, physiological, and connectivity abnormalities. Whether motor dysfunction arises from ChI degeneration, dysfunction of surviving ChI, or altered cholinergic signaling elsewhere in the striatal circuit remains unknown. Here, we distinguish these mechanisms using complementary genetic, pharmacological, and cell-ablation approaches. Surviving ChI became hyperactive coincident with the emergence of neurodegeneration and abnormal movements. Selective prenatal restoration of torsinA in ChI prevented their degeneration and reduced abnormal movements, identifying ChI as an important cellular locus of torsinA-dependent motor dysfunction. Systemic antimuscarinic treatment during juvenile striatal maturation produced persistent behavioral improvement outlasting treatment without preventing ChI degeneration. Direct intrastriatal antimuscarinic administration nearly abolished abnormal movements, identifying the striatum as a critical site of therapeutic action. Surprisingly, extensive ablation of the remaining dorsal striatal ChI neither prevented nor ameliorated abnormal movements and did not diminish the efficacy of systemic or intrastriatal antimuscarinic treatment. Thus, torsinA-dependent ChI pathology contributes causally to motor dysfunction, yet the continued presence of dorsal striatal ChI is not required for either expression of the motor phenotype or its suppression by muscarinic antagonists. These findings dissociate a developmental contribution of ChI pathology from the striatal mechanisms through which antimuscarinic drugs suppress dystonia-related movements.

neuroscience↗

bioRxiv2023

TorsinA is essential for the timing and localization of neuronal nuclear pore complex biogenesis

Nuclear pore complexes (NPCs) regulate information transfer between the nucleus and cytoplasm. NPC defects are linked to several neurological diseases, but the processes governing NPC biogenesis and spatial organization are poorly understood. Here, we identify a temporal window of strongly upregulated NPC biogenesis during neuronal maturation. We demonstrate that the AAA+ protein torsinA, whose loss of function causes the neurodevelopmental movement disorder DYT-TOR1A (DYT1) dystonia, coordinates NPC spatial organization during this period without impacting total NPC density. Using a new mouse line in which endogenous Nup107 is Halo-Tagged, we find that torsinA is essential for correct localization of NPC formation. In the absence of torsinA, the inner nuclear membrane buds excessively at sites of mislocalized, nascent NPCs, and NPC assembly completion is delayed. Our work implies that NPC spatial organization and number are independently regulated and suggests that torsinA is critical for the normal localization and assembly kinetics of NPCs.

cell biology↗

bioRxiv2022

Hepatocytes deficient in nuclear envelope protein lamina-associated polypeptide 1 are an ideal mammalian system to study intranuclear lipid droplets

Lipid droplets (LDs) are generally considered to be synthesized in the ER and utilized in the cytoplasm. However, LDs have been observed inside nuclei in some cells, although recent research on nuclear LDs has focused on cultured cell lines. To better understand nuclear LDs that occur in vivo, here we examined LDs in primary hepatocytes from mice following depletion of the nuclear envelope protein lamina-associated polypeptide 1 (LAP1). Microscopic image analysis showed that LAP1-depleted hepatocytes contain frequent nuclear LDs, which differ from cytoplasmic LDs in their associated proteins. We found type 1 nucleoplasmic reticula, which are invaginations of the inner nuclear membrane, are often associated with nuclear LDs in these hepatocytes. Furthermore, in vivo depletion of the nuclear envelope proteins lamin A and C from mouse hepatocytes led to severely abnormal nuclear morphology, but significantly fewer nuclear LDs than were observed upon depletion of LAP1. In addition, we show both high fat diet feeding and fasting of mice increased cytoplasmic lipids in LAP1-depleted hepatocytes, but reduced nuclear LDs, demonstrating a relationship of LD formation with nutritional state. Finally, depletion of microsomal triglyceride transfer protein did not change the frequency of nuclear LDs in LAP1-depleted hepatocytes, suggesting that it is not necessary for the biogenesis of nuclear LDs in these cells. Together, these data show that LAP1-depleted hepatocytes represent an ideal mammalian system to investigate the biogenesis of nuclear LDs and their partitioning between the nucleus and cytoplasm in response to changes in nutritional state and cellular metabolism in vivo.

cell biology↗

bioRxiv2021

A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding

Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in THAP1 encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Here, we demonstrate that the F81L mutation (THAP1F81L) impairs THAP1 transcriptional activity and disrupts CNS myelination. Strikingly, THAP1F81L exhibits normal DNA binding but causes a significantly reduced DNA binding of YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression. Our results suggest a model of molecular pathogenesis whereby THAP1F81L normally binds DNA but is unable to efficiently organize an active transcription complex.

neuroscience↗

bioRxiv2020

The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinsons Disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (Tripartite Motif Family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-920, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "Regulatory Loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL serves as a molecular switch controlling LRRK2s association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 modulates LRRK2s interaction with Rab29 and prevents upregulation of LRRK2 kinase activity by Rab29 in an E3-ligase-dependent manner. Finally, TRIM1 rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, controlling its degradation, localization, binding partners, kinase activity, and cytotoxicity.

molecular biology↗

bioRxiv2020

THAP1 Modulates Oligodendrocyte Maturationby Regulating ECM Degradation in Lysosomes

Mechanisms controlling myelination during CNS maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates ECM composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1-/- OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an auto-inhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding {beta}-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing {beta}-glucuronidase rescues Thap1-/- OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.

neuroscience↗

bioRxiv2019

TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models

Genetic redundancy can be exploited to identify therapeutic targets for inherited disorders. An example is DYT1 dystonia, a neurodevelopmental movement disorder caused by a loss-of-function (LOF) mutation in the TOR1A gene encoding torsinA. Prior work demonstrates that torsinA and its paralog torsinB have conserved functions at the nuclear envelope. This work established that low neuronal levels of torsinB dictate the neuronal selective phenotype of nuclear membrane budding. Here, we examined whether torsinB expression levels impact the onset or severity of abnormal movements, or neuropathological features in DYT1 mouse models. We demonstrate that torsinB levels bidirectionally regulate these phenotypes. Reducing torsinB levels causes a dosedependent worsening whereas torsinB overexpression rescues torsinA LOF-mediated abnormal movements and neurodegeneration. These findings identify torsinB as a potent modifier of torsinA LOF phenotypes and suggest that augmentation of torsinB expression level may retard or prevent symptom development in DYT1 dystonia.

neuroscience↗