AMPA Receptor Surface Expression Is Regulated by S-Nitrosylation of Thorase and Transnitrosylation of NSF

Umanah et al. show that the S-nitrosylation of Thorase and the transnitrosylation of NSF are responsible for NMDAR-activated trafficking of AMPARs underlying synaptic plasticity. © 2020 The Author(s) The regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking affects multiple brain functions, such as learning and memory. We have previously shown that Thorase plays an important role in the internalization of AMPARs from the synaptic membrane. Here, we show that N-methyl-D-aspartate receptor (NMDAR) activation leads to increased S-nitrosylation of Thorase and N-ethylmaleimide-sensitive factor (NSF). S-nitrosylation of Thorase stabilizes Thorase-AMPAR complexes and enhances the internalization of AMPAR and interaction with protein-interacting C kinase 1 (PICK1). S-nitrosylated NSF is dependent on the S-nitrosylation of Thorase via trans-nitrosylation, which modulates the surface insertion of AMPARs. In the presence of the S-nitrosylation-deficient C137L Thorase mutant, AMPAR trafficking, long-term potentiation, and long-term depression are impaired. Overall, our data suggest that both S-nitrosylation and interactions of Thorase and NSF/PICK1 are required to modulate AMPAR-mediated synaptic plasticity. This study provides critical information that elucidates the mechanism underlying Thorase and NSF-mediated trafficking of AMPAR complexes. © 2020 The Author(s)1

PINK1: from enzymatic function to modeling Parkinson’s disease

The loss of PTEN-Induced Kinase 1 (PINK1) is the second most common cause of autosomal recessive Parkinson’s disease. PINK1 has been shown to play an important role in mitochondrial quality control by regulating the function of Parkin, an E3 ubiquitin ligase also linked to autosomal recessive Parkinson’s disease. Aside from its regulation of Parkin, the role of PINK1 phosphorylation is not yet well understood and very few PINK1 substrates are known. Here, we identified 204 in vitro PINK1 substrates by using protein microarrays. Characterization of the PINK1 phosphorylome yielded novel substrates that suggest that PINK1 may play an even broader role in the regulation of cellular ubiquitination than previously understood. We also identified a novel way in which PINK1 may modulate Parkin ubiquitination activity. Furthermore, we have established novel human dopaminergic neuron models of loss of PINK1. Characterizing these cells will further our understanding of the pathogenesis of Parkinson’s disease in a disease-relevant model system

PINK1: from enzymatic function to modeling Parkinson’s disease

The loss of PTEN-Induced Kinase 1 (PINK1) is the second most common cause of autosomal recessive Parkinson’s disease. PINK1 has been shown to play an important role in mitochondrial quality control by regulating the function of Parkin, an E3 ubiquitin ligase also linked to autosomal recessive Parkinson’s disease. Aside from its regulation of Parkin, the role of PINK1 phosphorylation is not yet well understood and very few PINK1 substrates are known. Here, we identified 204 in vitro PINK1 substrates by using protein microarrays. Characterization of the PINK1 phosphorylome yielded novel substrates that suggest that PINK1 may play an even broader role in the regulation of cellular ubiquitination than previously understood. We also identified a novel way in which PINK1 may modulate Parkin ubiquitination activity. Furthermore, we have established novel human dopaminergic neuron models of loss of PINK1. Characterizing these cells will further our understanding of the pathogenesis of Parkinson’s disease in a disease-relevant model system

Neurologic Complications of Cancer Immunotherapy

Immunotherapy has revolutionized cancer treatment over the past decade. As it is increasingly introduced into routine clinical practice, immune-related complications have become more frequent. Accurate diagnosis and treatment are essential, with the goal of reduced patient morbidity. This review aims to discuss the various clinical manifestations, diagnosis, treatments, and prognosis of neurologic complications associated with the use of immune checkpoint inhibitors, adoptive T-cell therapies, and T-cell redirecting therapies. We also outline a suggested clinical approach related to the clinical use of these agents.Medicine, Faculty ofNon UBCMedicine, Department ofReviewedFacultyResearche

PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival

Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal-recessive Parkinson’s disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746) that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) promoter activity. Here, we show that PARIS links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity, as well as repression of PGC-1α promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Altogether, these results uncover a function of PINK1 to direct parkin-PARIS-regulated PGC-1α expression and dopaminergic neuronal survival

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.</p