In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson's disease
HUMAN MOLECULAR GENETICS
2018; 27 (22): 3974–85
Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss. At present, there are no drugs that stop the progression of PD. As with other multifactorial genetic disorders, genome-wide association studies (GWASs) found multiple risk loci for PD, although their clinical significance remains uncertain. Here, we report the identification of candidate drugs for PD by a method using GWAS data and in silico databases. We identified 57 Food and Drug Administration-approved drug families as candidate neuroprotective drugs for PD. Among them, dabrafenib, which is known as a B-Raf kinase inhibitor and is approved for the treatment of malignant melanoma, showed remarkable cytoprotective effects in neurotoxin-treated SH-SY5Y cells and mice. Dabrafenib was found to inhibit apoptosis, and to enhance the phosphorylation of extracellular signal-regulated kinase (ERK), and inhibit the phosphorylation of c-Jun NH2-terminal kinase. Dabrafenib targets B-Raf, and we confirmed a protein-protein interaction between B-Raf and Rit2, which is coded by RIT2, a PD risk gene in Asians and Caucasians. In RIT2-knockout cells, the phosphorylation of ERK was reduced, and dabrafenib treatment improved the ERK phosphorylation. These data indicated that dabrafenib exerts protective effects against neurotoxicity associated with PD. By using animal model, we confirmed the effectiveness of this in silico screening method. Furthermore, our results suggest that this in silico drug screening system is useful in not only neurodegenerative diseases but also other common diseases such as diabetes mellitus and hypertension.
View details for DOI 10.1093/hmg/ddy279
View details for Web of Science ID 000452535200012
View details for PubMedID 30137437
View details for PubMedCentralID PMC6216208
Stress response silencing by an E3 ligase mutated in neurodegeneration.
Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.
View details for DOI 10.1038/s41586-023-06985-7
View details for PubMedID 38297121
View details for PubMedCentralID 8997189
Endocytosis in the axon initial segment maintains neuronal polarity.
Neurons are highly polarized cells that face the fundamental challenge of compartmentalizing a vast and diverse repertoire of proteins in order to function properly1. The axon initial segment (AIS) is a specialized domain that separates a neuron's morphologically, biochemically and functionally distinct axon and dendrite compartments2,3. How the AIS maintains polarity between these compartments is not fully understood. Here we find that in Caenorhabditis elegans, mouse, rat and human neurons, dendritically and axonally polarized transmembrane proteins are recognized by endocytic machinery in the AIS, robustly endocytosed and targeted to late endosomes for degradation. Forcing receptor interaction with the AIS master organizer, ankyrinG, antagonizes receptor endocytosis in the AIS, causes receptor accumulation in the AIS, and leads to polarity deficits with subsequent morphological and behavioural defects. Therefore, endocytic removal of polarized receptors that diffuse into the AIS serves as a membrane-clearance mechanism thatis likely to work in conjunction with the known AIS diffusion-barrier mechanism to maintain neuronal polarity on the plasma membrane. Our results reveal a conserved endocytic clearance mechanism in the AIS to maintain neuronal polarity by reinforcing axonal and dendritic compartment membrane boundaries.
View details for DOI 10.1038/s41586-022-05074-5
View details for PubMedID 35978188
Japanese WDR45 de novo mutation diagnosed by exome analysis: A case report
NEUROLOGY AND CLINICAL NEUROSCIENCE
2017; 5 (4): 131–33
A 40-year-old Japanese woman presented with slowly progressing parkinsonism in adulthood. She had a history of epilepsy with intellectual disability in childhood. In a head magnetic resonance scan, T2-weighted imaging showed low signal intensity areas in the globus pallidus and the substantia nigra; T1-weighted imaging showed a halo in the nigra. Because the patient's symptoms and history were similar to those of patients with neurodegeneration with brain iron accumulation, we ran an exome analysis to investigate neurodegeneration with brain iron accumulation-associated genes. We identified a c.700 C>T (p.Arg 234*) mutation in exon 9 of the WDR45 gene, which had not been reported in Japanese patients with beta-propeller protein-associated neurodegeneration (a neurodegeneration with brain iron accumulation subtype). Sanger sequencing confirmed a heterozygous mutation in this patient that was absent in both her parents, so it was judged to be a de novo nonsense mutation.
View details for DOI 10.1111/ncn3.12132
View details for Web of Science ID 000405592700008
View details for PubMedID 28932395
View details for PubMedCentralID PMC5575553
Less Limb Muscle Involvement in Myositis Patients with Anti-Mitochondrial Antibodies
2017; 78 (5-6): 290–95
Recent studies have revealed the clinical, histological, and pathophysiological characteristics in a group of inflammatory myopathies with selected autoantibodies. We retrospectively compared the clinical manifestations and histological features between 8 anti-mitochondrial (anti-M2) antibody-positive and 33 antibody-negative patients. Patients with anti-M2 antibodies have been previously reported to have delayed diagnostic confirmation and frequent cardiopulmonary complications in comparison to those without the antibodies. In our study, clinical characteristics in patients with the antibodies were as follows: lesser degree of limb muscle weakness and atrophy as well as lymphocytic infiltration in muscle biopsy specimens, and frequent paravertebral muscle atrophy. Anti-M2 antibody appeared to be a biomarker related to not only cardiopulmonary complications, but also characteristic -distributions of affected muscles.
View details for DOI 10.1159/000481503
View details for Web of Science ID 000416225300010
View details for PubMedID 29049993
Radiographic occult cerebellar germinoma presenting with progressive ataxia and cranial nerve palsy
2016; 16: 4
Although the usefulness of susceptibility-weighted imaging (SWI) for detecting basal ganglia germinoma has been reported, the technique is not widely used. We recently encountered an unusual case of primary cerebellar germinoma, presenting with progressive ataxia and cranial nerve palsy, characterized by gradually enlarging low-intensity lesions visible with both T2*-weighted imaging (T2*WI), which were the key to the diagnosis.A 30-year-old man was referred to our hospital because of slowly progressive dizziness and mild ataxia. Magnetic resonance imaging (MRI) revealed a small, low-intensity spot in the left cerebellar peduncle on the T2*WI and SWI without enhancement. Cerebral angiography revealed no vascular abnormality. The serum α-fetoprotein value was normal. A steroid-pulse was administered as a therapeutic and diagnostic trial, but the symptoms improved little. The patient was discharged from the hospital but soon developed brainstem dysfunction, characterized by dyspnea or hiccups, and he was readmitted. T2*WI imaging revealed expanded and extended spotty lesions in the cerebellum and brainstem, which had not enhanced with contrast agent previously. Targeted stereotactic biopsy of the newly enhanced cerebellar lesion was performed; histopathological examination of the tissue revealed pure germinoma. Serum and cerebral spinal fluid values of beta-human chorionic gonadotropin were not significantly elevated. Chemotherapy with carboplatin and etoposide was initiated. The enhanced lesion disappeared promptly, but the patient continued to require assisted automatic ventilation because of paralysis of respiratory muscles.We conclude that enlarging low-intensity lesions on T2*WI and SWI may be a reliable clue to the diagnosis of germinomas, irrespective of their location, even without enhancement. Biopsy of the tumor at an early stage is the only way to make the diagnosis conclusively and enable prompt start of treatment.
View details for DOI 10.1186/s12883-015-0516-9
View details for Web of Science ID 000368393400002
View details for PubMedID 26759273
View details for PubMedCentralID PMC4709897
[Medial longitudinal fasciculus (MLF) syndrome in a patient with giant cell arteritis].
Rinsho shinkeigaku = Clinical neurology
2015; 55 (2): 107–10
A 76-year-old female was referred to our department because of diplopia for two months and intermittent claudication for five months. She showed medial longitudinal fasciculus (MLF) syndrome. Brain MRI (T2WI) showed multiple infarctions in the right pontine tegmentum and left paramedian midbrain. A biopsy of superficial temporal artery showed the characteristic findings of glanulomatous inflammation indicative of giant cell arteritis. We thought the mechanism of this cerebral infarction as artery to artery embolization or intracranial arteritis. Treatment with oral prednisolone (1 mg/kg/day) improved her limb claudication and normalized serum C-reactive protein level.
View details for DOI 10.5692/clinicalneurol.55.107
View details for PubMedID 25746074
Myositis with antimitochondrial antibodies diagnosed by rectus abdominis muscle biopsy
MUSCLE & NERVE
2013; 47 (5): 766–68
Antimitochondrial antibodies are autoantibodies detected in 90% of primary biliary cirrhosis (PBC) patients. Some PBC cases are complicated by myositis, which is difficult to confirm due to minimal histological evidence of inflammation in limb muscles.Our aim was to determine the extent of inflammatory changes in a truncal muscle biopsy specimen from a PBC patient.A 48-year-old woman with a 5-year history of atrial fibrillation and chronic heart failure was evaluated for elevated serum creatine kinase level. Antimitochondrial M2 antibodies were detected, and PBC was diagnosed. A biceps brachii biopsy specimen showed mild, non-specific myogenic changes; a second biopsy was performed on the rectus abdominis muscle, which showed typical inflammatory changes. Myositis with antimitochondrial M2 antibodies was confirmed.In myositis patients with antimitochondrial M2 antibodies, muscles of the extremities are involved to a lesser extent. Radiological and histological examination focusing on truncal muscles, including a biopsy, is important.
View details for DOI 10.1002/mus.23730
View details for Web of Science ID 000318234200019
View details for PubMedID 23553600
[Reversible cerebral vasoconstriction syndrome in a stroke patient with systemic lupus erythematosus and antiphospholipid antibody].
Rinsho shinkeigaku = Clinical neurology
2013; 53 (4): 283–86
A 36-year-old female with systemic lupus erythematosus and antiphospholipid syndrome was referred to our department because of mild weakness of left arm and an episode of right amaurosis fugax for twenty days. Brain MRI showed right ACA/MCA/PCA border zone infarction on DWI/T2WI/FLAIR and MR angiography (MRA) showed multiple segmental stenosis in right internal carotid artery, right and left middle cerebral artery, and bilateral posterior cerebral arteries. Treatment with oral aspirin (100 mg/day) and continuous infusion of heparin kept her neurological symptoms and signs stable. MRA on 28 days revealed complete recovery of multiple stenotic lesions, thus, diagnosis of reversible cerebral vasoconstriction (RCVS) was made. RCVS should be considered as a cause of neurological deficit in patients with SLE regardless of thunderclap headache.
View details for PubMedID 23603542
Brain Imaging Modality before Systemic Thrombolysis for Ischemic Stroke within Three Hours
2010; 64 (4): 241–45
In Japan, MRI-based thrombolysis after CT screening is the most common imaging strategy prior to intravenous thrombolysis (IVT) with tissue plasminogen activator (tPA) within 3 h after ischemic stroke. A choice of MRI with MR angiography (MRA) provides a higher diagnostic accuracy, but may delay an initiation of thrombolysis.In our neuro-unit, brain CT is the first screening image for suspected stroke. We retrospectively examined a delay to thrombolysis, imaging modality, diagnostic accuracy, and clinical outcomes at 3 months by the modified Rankin Scale in patients receiving IVT within 3 h.Among 67 patients receiving IVT with tPA, brain imaging prior to IVT was solely CT in 10 (15%) patients and CT + MRI/MRA in 57 (85%) patients. Final diagnosis of brain ischemia was 100%. Patients receiving CT + MRI had significantly shorter pre-hospital delay (mean 54 vs. 83 min; p = 0.012), but longer door-to-needle time (mean 90 vs. 57 min; p = 0.019) than those receiving CT only. Finally, time from onset to thrombolysis was not different between the two groups and clinical outcomes were also comparable. The earlier patients arrived, the longer door-to-needle times were (p < 0.001).The imaging strategy of initial CT screening with optional MRI/MRA scans prior to IVT was feasible. However, it resulted in an additional 30 min in-hospital delay of tPA administration, which may affect clinical outcomes.
View details for DOI 10.1159/000319918
View details for Web of Science ID 000281903200009
View details for PubMedID 20820106