Extracellular transportation of α-synuclein by HLA class II molecules.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of α-synuclein aggregates in form of Lewy bodies. Genome-wide association studies have revealed that human leukocyte antigen (HLA) class II is a PD-associated gene, although the mechanisms linking HLA class II and PD remain elusive. Here, we identified a novel function of HLA class II in the transport of intracellular α-synuclein to the outside of cells. HLA class II molecules and α-synuclein formed complexes and moved to the cell surface at various degrees among HLA-DR alleles. HLA-DR with a DRB5∗01:01 allele, a putative PD-risk allele, substantially translocated normal and conformationally abnormal α-synuclein to the cell surface and extracellular vesicles. α-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic α-synuclein and HLA-DR with DRB5∗01:01. Our findings will expand our knowledge of unconventional HLA class II function from autoimmune diseases to neurodegenerative disorders, shedding light on the association between the GWAS-prioritized PD-risk gene HLA-DR and α-synuclein.

[A case of high cervical cord infarction presenting with cardiopulmonary arrest due to respiratory dysfunction].

A 46-year-old man with neck pain and impaired physical mobility called for emergency medical services. The patient was able to communicate with the emergency medical team upon their arrival. However, he went into cardiopulmonary arrest 5 minutes later. Cardiopulmonary resuscitation was immediately performed, and the patient was admitted to our hospital with a Glasgow Coma Scale score of E1V1M1. His respiratory rate was 5 breaths/minute and his partial pressure of carbon dioxide in arterial blood (PaCO2) was 127 |mmHg, necessitating intubation and ventilation. His consciousness improved as the PaCO2 level decreased. However, he was unable to be weaned off the ventilator and breathe independently. Neurological examination revealed flaccid quadriplegia, pain sensation up to the C5 level, absence of deep tendon reflexes, indifferent plantar responses, and absence of the rectoanal inhibitory reflex. Magnetic resonance imaging showed a hyperintense lesion with slight enlargement of the anterior two-thirds of the spinal cord at the C2-C4 level on both T2-weighted and diffusion-weighted images, consistent with a diagnosis of spinal cord infarction. Although the quadriplegia and sensory loss partially improved, the patient was unable to be weaned from the ventilator. Cervical cord infarction of the anterior spinal artery can cause rapid respiratory failure leading to cardiopulmonary arrest. Therefore, cervical cord infarction should be included as a differential diagnosis when examining patients after cardiopulmonary resuscitation.

Ischemic Stroke Due to Heparin-induced Thrombocytopenia during Severe COVID-19 Infection.

A 53-year-old woman with severe coronavirus disease 2019 (COVID-19) pneumonia was admitted and treated with intravenous unfractionated heparin for thromboprophylaxis under general anesthesia with mechanical ventilation. She developed right hemiparesis after hospitalization due to a large hemorrhagic infarction. Her platelet count decreased from 243,000/µL at administration to 121,000/µL. Anti-platelet factor 4-heparin antibody testing was positive according to a latex immunoturbidimetric assay. She was therefore diagnosed with heparin-induced thrombocytopenia. We immediately stopped the heparin and started argatroban; the platelet count recovered, and thrombosis did not relapse. Physicians should consider heparin-induced thrombocytopenia as a cause of ischemic stroke in patients with COVID-19 infection.

piRNA/PIWI Protein Complex as a Potential Biomarker in Sporadic Amyotrophic Lateral Sclerosis.

The pathological hallmark of the majority of amyotrophic lateral sclerosis (ALS) cases is the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43), an RNA-binding protein. Several studies have attributed disease processes of ALS to abnormal RNA metabolism. However, dysregulated biogenesis of RNA, especially non-coding RNA (ncRNA), is poorly understood. To resolve it, RNA-Seq, biochemical, and immunohistochemical analyses were performed on the pyramidal tract of the medulla oblongata of sporadic ALS (sALS) and control postmortem brain samples. Here, we report perturbation of ncRNA biogenesis in PIWI-interacting RNA (piRNA) in several sALS brain samples associated with TDP-43 pathology. In addition, we confirmed the dysregulation of two PIWI homologs, PIWI-like-mediated gene silencing 1 (PIWIL1) and PIWIL4, which bind to piRNAs to regulate their expression. PIWIL1 was mislocalized and co-localized with TDP-43 in motor neurons of sporadic ALS lumbar cords. Our results imply that dysregulation of piRNA, PIWIL1, and PIWIL4 is linked to pathogenesis of ALS. Based on these results, piRNAs and PIWI proteins are potential diagnostic biomarkers and therapeutic targets of ALS.