Ribosome Profiling and Mass Spectrometry Reveal Widespread Mitochondrial Translation Defects in a Striatal Cell Model of Huntington Disease.

Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric, cognitive deficits, and choreiform movements. Multiple lines of evidence point to an association between HD and aberrant striatal mitochondrial functions; however, the present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We found that protein synthesis is diminished in HD mitochondria compared to healthy control striatal cell models.

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.

RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network ("Rhesactome") in the striatum.

The striatum of the brain coordinates motor function. Dopamine-related drugs may be therapeutic to patients with striatal neurodegeneration, such as Huntington's disease (HD) and Parkinson's disease (PD), but these drugs have unwanted side effects. In addition to stimulating the release of norepinephrine, amphetamines, which are used for narcolepsy and attention-deficit/hyperactivity disorder (ADHD), trigger dopamine release in the striatum.

SERBP1 Is a Component of the Liver Receptor Homologue-1 Transcriptional Complex.

Liver receptor homologue-1 (LRH1) is an orphan nuclear receptor that has been shown to play a role in the transcriptional regulation of pathways involved in cancer. Elucidating the components of the LRH1 transcriptional complex to better understand endogenous regulation of the receptor as well as its role in cancer remains a high priority. A sub-cellular enrichment strategy coupled with proteomic approaches was employed to identify putative LRH1 co-regulators.

Software Analysis of Uncorrelated MS1 Peaks for Discovery of Post-Translational Modifications.

The goal in proteomics to identify all peptides in a complex mixture has been largely addressed using various LC MS/MS approaches, such as data dependent acquisition, SRM/MRM, and data independent acquisition instrumentation. Despite these developments, many peptides remain unsequenced, often due to low abundance, poor fragmentation patterns, or data analysis difficulties. Many of the unidentified peptides exhibit strong evidence in high resolution MS(1) data and are frequently post-translationally modified, playing a significant role in biological processes.