Speaker: Prof. Aaron D. Gitler (Stanford University)

Time: 13:00 - 14:30 p.m., Mar 11, 2025, GMT+8

Venue: Youcai Deng Lecture Hall, School of Life Sciences, PKU

Abstract: 

Hausdorff dimension is a positive real number that quantifies the size of fractal sets. In many cases this value isn't explicitly known, but can be estimated with different levels of accuracy (depending on the method used). We will describe applications to different areas of mathematics, including number theory, geometry and dynamical systems.Amyotrophic lateral sclerosis is a devastating human neurodegenerative disease caused by a selective loss of motor neurons from the brain and spinal cord. Intriguingly, in ALS, some motor neurons are vulnerable and others are resistant. We used single-cell transcrptomics and epigenomics to explore the heterogeneity of the spinal cord and to discover the changes that occur during ALS. We identified differentially expressed genes associated with degeneration as well as resilience. Our studies have revealed unexpected diversity in the autonomic nervous system, gradients of fast-and slow-firing motor neuron types within motor pools. These findings provide insight into mechanisms of degeneration, molecular underpinnings of selective vulnerability, and may suggest novel therapeutic strategies. We have also been extending studies on the adult human spinal cord, revealing similar logic as in mouse motor neurons, as well as novel human specific features.

We also use single cell approaches to define the RNA processing changes associated with ALS pathology. A hallmark pathological feature of ALS is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord. We discovered that TDP-43 represses a cryptic exon splicing event in the ALS risk gene UNC13A. Loss of TDP-43 from the nucleus causes inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. Our data provide a direct functional link between one of the strongest genetic risk factors for ALS UNC13A genetic variant and loss of TDP-43 function. We are also using genome wide approaches to identify genes that work with TDP-43 to regulate cryptic splicing. Beyond cryptic splicing, we have also discovered loss of TDP-43 in ALS leads to widespread alternative polyadenylation changes, impacting expression of disease-relevant genes and providing evidence that alternative polya-denylation is a new facet of TDP-43 pathology.

Source: McGovern Institute for Brain Research at PKU