Molecular Biology seminars

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing. By re-analyzing RNA-sequencing datasets from human FTD/ALS brains, we discovered dozens of novel cryptic splicing events in important neuronal genes. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies, but how those variants increase risk for disease is unknown. We discovered that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harboring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function. Recent analyses have revealed even further changes in TDP-43 target genes, including widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.

Alpha synuclein and Lrrk2 are key players in Parkinson's disease and related disorders, but their normal role has been confusing and controversial. Data from acute gene-editing based knockdown, followed by functional assays, will be presented.

In the fifth of this year’s Brain Prize webinars, Emily Osterweil (Harvard Medical School, USA), Gary Bassell (Emory University, USA) and Giovanna Mallucci (Altos Labs, UK) will present their work on dysfunctional translation in disease. Each speaker will present for 25 minutes, and the webinar will conclude with an open discussion. The webinar will be moderated by two of the winners of the 2023 Brain Prize, Michael Greenberg and Erin Schuman.

In the second of this year’s Brain Prize webinars, Rob Singer (Einstein Medical College, USA), Florence Besse (Institut de Biologie Valrose, France) and Jennifer Lippincott-Schwartz (Janelia Farm Research Campus, USA) will present their work on mRNA transport, trafficking, and localization. Each speaker will present for 25 minutes, and the webinar will conclude with an open discussion. The webinar will be moderated by the winners of the 2023 Brain Prize, Michael Greenberg, Erin Schuman and Christine Holt.

The complex morphology of neurons, with synapses located hundreds of microns from the cell body, necessitates the localization of important cell biological machines, including ribosomes, within dendrites and axons. Local translation of mRNAs is important for the function and plasticity of synapses. Using advanced sequencing and imaging techniques we have updated our understanding of the local transcriptome and identified the local translatome- identifying over 800 transcripts for which local translation is the dominant source of protein. In addition, we have explored the unique mechanisms neurons use to meet protein demands at synapses, identifying surprising features of neuronal and synaptic protein synthesis.

Understanding the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. We discuss our work using multi-omics methods to provide mechanistic and functional insights into how addiction perturbs gene regulatory programs in the rat brain, with single-cell resolution.