Opposing roles of p38α-mediated phosphorylation and arginine methylation in driving TDP-43 proteinopathy

bioRxiv (Cold Spring Harbor Laboratory) · 2021 · 10 citations

• Cell biology
• Biology
• Chemistry

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we demonstrate that inhibition of p38α MAPK reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. We establish that p38α MAPK phosphorylates TDP-43 at pathological serine 409/410 (S409/S410) and serine 292 (S292), which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we show that protein arginine methyltransferase 1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.

Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons

Nature Neuroscience · 2021 · 211 citations

• Neuroscience
• Biology
• Genetics

Single-cell transcriptomic analysis of the adult mouse spinal cord

bioRxiv (Cold Spring Harbor Laboratory) · 2020 · 9 citations

• Neuroscience
• Biology
• Genetics

Abstract The spinal cord is a fascinating structure responsible for coordinating all movement in vertebrates. Spinal motor neurons control the activity of virtually every organ and muscle throughout the body by transmitting signals that originate in the spinal cord. These neurons are remarkably heterogeneous in their activity and innervation targets. However, because motor neurons represent only a small fraction of cells within the spinal cord and are difficult to isolate, the full complement of motor neuron subtypes remains unknown. Here we comprehensively describe the molecular heterogeneity of motor neurons within the adult spinal cord. We profiled 43,890 single-nucleus transcriptomes using fluorescence-activated nuclei sorting to enrich for spinal motor neuron nuclei. These data reveal a transcriptional map of the adult mammalian spinal cord and the first unbiased characterization of all transcriptionally distinct autonomic and somatic spinal motor neuron subpopulations. We identify 16 sympathetic motor neuron subtypes that segregate spatially along the spinal cord. Many of these subtypes selectively express specific hormones and receptors, suggesting neuromodulatory signaling within the autonomic nervous system. We describe skeletal motor neuron heterogeneity in the adult spinal cord, revealing numerous novel markers that distinguish alpha and gamma motor neurons—cell populations that are specifically affected in neurodegenerative disease. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neurons. Collectively, these data provide a single-cell transcriptional atlas for investigating motor neuron diversity as well as the cellular and molecular basis of motor neuron function in health and disease.

BraInMap Elucidates the Macromolecular Connectivity Landscape of Mammalian Brain

Cell Systems · 2020 · 85 citations

• Neuroscience
• Computational biology
• Biology