FAU-Brain Institute
Our Research Publications
Welcome to our collection of research publications. Explore our latest findings and discoveries in the field of neurodegenerative diseases. Our publications provide insights into the signaling networks and potential therapeutic developments for these disorders.
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RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease
The therapeutic effects of l-3,4-dihydroxyphenylalanine (l-DOPA) in patients with Parkinson’s disease (PD) severely diminishes with the onset of abnormal involuntary movement, l-DOPA–induced dyskinesia (LID). However, the molecular mechanisms that promote LID remain unclear. Here, we demonstrated that RasGRP1 [(guanine nucleotide exchange factor (GEF)] controls the development of LID. l-DOPA treatment rapidly up-regulated RasGRP1 in the striatum of mouse and macaque model of PD. We applied High-resolution tandem mass spectrometry and identified additional RasGRP1 downstream targets linked to LID vulnerability that could be targeted to diminish LID. Science Advances, Vol 6. Issue 18. Mar 2020
Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease
The polyglutamine expansion of huntingtin (mHTT) causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear. Here, we found that mHtt promotes ribosome stalling and suppresses protein synthesis in mouse HD striatal neuronal cells. We applied high-resolution global ribosome footprint profiling (Ribo-Seq) for the first time in striatal neuronal cells that indicates a widespread shift in ribosome occupancy toward the 5' and 3' end and unique single-codon pauses on selected mRNA targets in HD cells, compared to controls. This study indicates mHtt impedes ribosomal translocation during translation elongation, a mechanistic defect that can be exploited for HD therapeutics. Nature Communications, Mar 5;12(1):1461, 2021
Rhes protein transits from neuron to neuron and facilitates mutant huntingtin spreading in the brain
Rhes (RASD2) is a thyroid hormone-induced gene that regulates striatal motor activity and promotes neurodegeneration in Huntington disease (HD) and tauopathy. Rhes moves and transports the HD protein, polyglutamine-expanded huntingtin (mHTT), via tunneling nanotube (TNT)-like membranous protrusions between cultured neurons. However, similar intercellular Rhes transportation in the intact brain was unknown. Here we report that Rhes is a first striatum-enriched protein move and transport mHTT between neurons and brain regions, providing new insights into interneuronal protein spread in the brain. Science Advances, Vol 8. Issue 12. 25 Mar 2022
Deletion of SUMO1 attenuates behavioral and anatomical deficits by regulating autophagic activities in Huntington disease
Previous studies have shown that SUMO1 (small ubiquitin-like modifier-1) modification of mHtt promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knockin mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. Depletion of SUMO diminished the mHtt levels and enhanced autophagy flux. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by regulating autophagy activities. Proc Natl Acad Sci U S A​. Feb 1; 119(5). 2022.
SUMO modifies GβL and mediates mTOR signaling
The mechanistic target of rapamycin (mTOR) signaling is influenced by multiple regulatory proteins and post-translational modifications; however, underlying mechanisms remain unclear. Here, we report a novel role of small ubiquitin-like modifier (SUMO) in mTOR complex assembly and activity. By investigating the SUMOylation status of core mTOR components, we observed that the regulatory subunit, GβL (G protein β-subunit-like protein, also known as mLST8), is modified by SUMO1, 2, and 3 isoforms, which influences the assembly of mTOR protein complexes, and regulates mTOR activity. Journal of Biological Chemistry. 300(4).105778, 2024.
Ribosome Profiling and Mass Spectrometry Reveal Widespread Mitochondrial Translation Defects in a Striatal Cell Model of Huntington Disease
Multiple lines of evidence point to an association between Huntington disease and aberrant striatal mitochondrial functions; however, the present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We utilized ribosome profiling (Ribo-Seq) to analyze detailed snapshots of ribosome occupancy of the mitochondrial mRNA transcripts in control and HD striatal cell models. The Ribo-Seq data revealed almost unaltered ribosome occupancy on the nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation, but, by contrast, ribosome occupancy was dramatically increased for mitochondrially encoded oxidative phosphorylation mRNAs. The tandem mass tag-based mass spectrometry lack of correlations between ribosome occupancy and actual mature mitochondrial protein products in HD, providing for the first time a clear evidence of a widespread dichotomous effect on ribosome occupancy and protein abundance of mitochondria-related genes in HD. Mol Cell Proteomics​. Apr;23(4):100746, 2024