eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS.

Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2α. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.

The molecular pathogenesis of repeat expansion diseases.

Expanded short tandem repeats in the genome cause various monogenic diseases, particularly neurological disorders. Since the discovery of a CGG repeat expansion in the FMR1 gene in 1991, more than 40 repeat expansion diseases have been identified to date. In the coding repeat expansion diseases, in which the expanded repeat sequence is located in the coding regions of genes, the toxicity of repeat polypeptides, particularly misfolding and aggregation of proteins containing an expanded polyglutamine tract, have been the focus of investigation. On the other hand, in the non-coding repeat expansion diseases, in which the expanded repeat sequence is located in introns or untranslated regions, the toxicity of repeat RNAs has been the focus of investigation. Recently, these repeat RNAs were demonstrated to be translated into repeat polypeptides by the novel mechanism of repeat-associated non-AUG translation, which has extended the research direction of the pathological mechanisms of this disease entity to include polypeptide toxicity. Thus, a common pathogenesis has been suggested for both coding and non-coding repeat expansion diseases. In this review, we briefly outline the major pathogenic mechanisms of repeat expansion diseases, including a loss-of-function mechanism caused by repeat expansion, repeat RNA toxicity caused by RNA foci formation and protein sequestration, and toxicity by repeat polypeptides. We also discuss perturbation of the physiological liquid-liquid phase separation state caused by these repeat RNAs and repeat polypeptides, as well as potential therapeutic approaches against repeat expansion diseases.

[Social maturity scores in adults with Down syndrome. Characteristics at the onset of Alzheimer's disease and changes by age group].

Age-specific characteristics and annual changes of social maturity in adults with Down syndrome (DS) were retrospectively investigated. Forty-six individuals aged 15-58 years were enrolled. Social age (SA) in all domains and subdomains was assessed using the revised S-M social maturity test. Thirty-four cases were evaluated for SA changes over time at 1 year. The SA of adult DS tended to be lower in those under 20 and over 42 years of age. The SA of adults with DS was lowest in the Socialization domain, and this trend was generally common across all age groups. The annual decline of SA was more prominent in the DS-AD group than in the non-DS-AD group. Annual decline of SA in the communication domain had the same discriminative power as that in the whole domains in the discrimination of DS-AD from non-DS-AD. These results are expected to contribute to the development of clinical diagnostic methods for DS-AD in the future.

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD.

The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.

Repeat-associated non-AUG translation in neuromuscular diseases: mechanisms and therapeutic insights.

Expanded short tandem repeats cause more than 50 monogenic diseases, which are mostly neuromuscular diseases. In the non-coding repeat expansion diseases, in which the expanded repeat sequence is located outside of the coding region, the toxicity of the transcribed repeat-containing RNAs had been the focus of research. However, recent studies have revealed that repeat RNAs can be translated into repeat polypeptides, despite the lack of an AUG initiation codon, by non-canonical repeat-associated non-AUG translation (RAN translation). RAN translated repeat polypeptides have actually been confirmed in patients' tissues. Moreover, various cellular and animal disease models have demonstrated the toxicity of these peptides, suggesting the pathogenic roles of RAN translation in the repeat expansion diseases. In this review, we will outline RAN translation, from the viewpoint of its molecular mechanisms to its potential as a therapeutic target for the repeat expansion diseases.

Serum leucine-rich α2 glycoprotein as a potential biomarker for systemic inflammation in Parkinson's disease.

There is ample epidemiological and animal-model evidence suggesting that intestinal inflammation is associated with the development of Parkinson's disease (PD). Leucine-rich α2 glycoprotein (LRG) is a serum inflammatory biomarker used to monitor the activity of autoimmune diseases, including inflammatory bowel diseases. In this study, we aimed to investigate whether serum LRG could be used a biomarker of systemic inflammation in PD and to help distinguish disease states. Serum LRG and C-reactive protein (CRP) levels were measured in 66 patients with PD and 31 age-matched controls. We found that serum LRG levels were statistically significantly higher in the PD group than in the control group (PD: 13.9 ± 4.2 ng/mL, control: 12.1 ± 2.7 ng/mL, p = 0.036). LRG levels were also correlated with Charlson comorbidity index (CCI) and CRP levels. LRG levels in the PD group were correlated with Hoehn and Yahr stages (Spearman's r = 0.40, p = 0.008). LRG levels were statistically significantly elevated in PD patients with dementia as compared to those without dementia (p = 0.0078). Multivariate analysis revealed a statistically significant correlation between PD and serum LRG levels after adjusting for serum CRP levels, and CCI (p = 0.019). We conclude that serum LRG levels could be considered a potential biomarker for systemic inflammation in PD.

FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD.

Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.

Temporal Changes in Brain Magnetic Resonance Imaging Findings over 16 Years in a Patient with Neuronal Intranuclear Inclusion Disease.

Leukoencephalopathy with high-intensity signals in the corticomedullary junction on diffusion-weighted imaging (DWI) is a diagnostic hallmark for neuronal intranuclear inclusion disease (NIID). We herein report a 65-year-old man who developed dementia and was diagnosed with NIID 2 years later. Of note, he had coincidentally undergone brain magnetic resonance imaging 14 and 10 years before the onset of dementia. No abnormalities were discerned on DWI on either of these occasions, but high-intensity signals in the corticomedullary junction on DWI were revealed two years before the clinical onset. The early recognition of this pathognomonic white matter change may facilitate the presymptomatic diagnosis of NIID.

Case Report: Dexmedetomidine for Intractable Clusters of Myoclonic Jerks and Paroxysmal Sympathetic Hyperactivity in Progressive Encephalomyelitis With Rigidity and Myoclonus.

Introduction: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder characterized by painful spasms, myoclonic jerks, hyperekplexia, brainstem dysfunction, and dysautonomia, which is sometimes resistant to γ-amino-butyric acid (GABA)-ergic agents. The response to immunotherapy varies depending on identified autoantibodies. We report a dramatic response to dexmedetomidine in a patient with glycine receptor (GlyR) antibody-positive PERM who developed intractable clusters of myoclonic jerks and paroxysmal sympathetic hyperactivity (PSH) that was highly refractory to conventional symptomatic treatment with GABAergic drugs and immunotherapy. Case Presentation: A 62-year-old Japanese man was transferred to our center for intermittent painful spasms that progressed in severity over the preceding 7 weeks. On admission, he had gaze-evoked nystagmus, and paroxysmal painful spasms/myoclonic jerks triggered by sound or touch. The myoclonic jerks rapidly worsened, along with the development of hyperekplexia, opisthotonus, and PSH, leading to prolonged apnea requiring mechanical ventilation. Brain and spinal cord magnetic resonance imaging was unremarkable. Cerebrospinal fluid (CSF) examination revealed mild pleocytosis and oligoclonal bands. Surface electromyography confirmed simultaneous agonist-antagonist continuous motor unit activity. Based on the clinico-electrophysiological features, PERM was suspected. He was initially treated with intravenous steroids, immunoglobulin, benzodiazepines, and propofol, but the symptoms persisted. On day 9, he received a continuous infusion of dexmedetomidine, which resulted in dramatic reduction in the frequency of clusters of myoclonic jerks and PSH. The effect of dexmedetomidine was confirmed by surface electromyography. The addition of plasma exchange resulted in further clinical improvement. GlyR antibodies were identified in the CSF but not the serum, leading to the diagnosis of GlyR antibody-positive PERM. Conclusions: PERM is an immune-mediated disorder, but dexmedetomidine, a highly selective α2-adrenergic agonist, may alleviate paroxysmal symptoms by decreasing noradrenergic neuronal activity, resulting in attenuation of antibody-mediated disinhibited increased motor and sympathetic activity. Dexmedetomidine may be useful as an adjunctive symptomatic therapy in PERM and related disorders.

Impaired age-dependent increases in phosphoglycerate kinase activity in red blood cells of Parkinson's disease patients.

BACKGROUND: Impaired bioenergetics are partially involved in the pathogenesis of Parkinson's disease (PD). Phosphoglycerate kinase (PGK), an essential enzyme for glycolysis, has recently attracted attention due to its pathogenic role in PD and as a target for disease-modifying therapies. This study is aimed to evaluate the profiles of PGK activity in red blood cells (RBCs) of PD patients and controls. METHODS: Sixty-eight PD patients and thirty-four age-matched unrelated controls were enrolled. PGK activities of RBCs were measured by the established colorimetric assay and standardized by the same RBC samples. RESULTS: PGK activity of the PD group was significantly higher than that of the control group in participants aged sixty-five years or younger, whereas it was not significantly different between the two groups at any age. PGK activity was positively correlated with aging in the control group, but this was not noted in the PD group. On multivariable analysis by partial correlation in the PD group, PGK activity was negatively correlated with the specific binding ratio of dopamine transporter scintigraphy in the striatum. The levodopa-equivalent daily dose was not significantly correlated with the enzyme activity. CONCLUSION: The results support the following: 1) elevation of PGK activities in RBCs can be detected in relatively young PD patients and with normal aging; 2) the degree of striatonigral degeneration is associated with elevated PGK activities. These are important considerations when the PGK assay is applied as a diagnostic biomarker of PD and to therapeutically monitor PGK-enhancing treatments.

Risk factors for neuropsychiatric symptoms in patients with Parkinson's disease during COVID-19 pandemic in Japan.

The worsening of neuropsychiatric symptoms such as depression, anxiety, and insomnia in patients with Parkinson's disease (PD) has been a concern during the COVID-19 pandemic, because most people worked in self-isolation for fear of infection. We aimed to clarify the impact of social restrictions imposed due to the COVID-19 pandemic on neuropsychiatric symptoms in PD patients and to identify risk factors associated with these symptoms. A cross-sectional, hospital-based survey was conducted from April 22, 2020 to May 15, 2020. PD patients and their family members were asked to complete paper-based questionnaires about neuropsychiatric symptoms by mail. PD patients were evaluated for motor symptoms using MDS-UPDRS part 2 by telephone interview. A total of 71 responders (39 PD patients and 32 controls) completed the study. Although there was no difference in the age distribution, the rate of females was significantly lower in PD patients (35%) than controls (84%) (P < 0.001). Participants with clinical depression (PHQ-9 score ≥ 10) were more common in PD patients (39%) than controls (6%) (P = 0.002). Multivariate logistic regression analysis revealed that an MDS-UPDRS part 2 score was correlated with the presence of clinical depression (PHQ-9 score ≥ 10) and clinical anxiety (GAD-7 score ≥ 7) (clinical depression: OR, 1.31; 95% CI, 1.04-1.66; P = 0.025; clinical anxiety: OR, 1.36; 95% CI, 1.07-1.72; P = 0.013). In the presence of social restrictions, more attention needs to be paid to the neuropsychiatric complications of PD patients, especially those with more severe motor symptoms.

Cerebral Infarction with Pulmonary Thromboembolism Due to Immobilization.

Arterial and venous thrombi can coexist without preexisting conditions, such as malignant disease, thrombotic predisposition, or arteriovenous shunt. We herein report a case of acute cerebral infarction and pulmonary thromboembolism in the absence of underlying disease. A 71-year-old woman presented with left hemiplegia. On an examination, her oxygen saturation was 91% on ambient air despite the absence of chest symptoms and clear lung fields on a chest radiograph. The patient was finally diagnosed with acute cerebral infarction caused by large artery atherosclerosis and acute pulmonary thromboembolism due to deep vein thrombosis, consequent to immobilization for three days after the onset of cerebral infarction.

[A case of hypertrophic pachymeningitis associated with probable sarcoidosis with increased serum IgG4].

We report a 54-year-old man, who presented with an acute onset of diplopia and ptosis on the left side. On admission, neurological examination showed left oculomotor and abducens nerve palsy. Brain MRI showed thickening of the left parieto-temporal dura mater with gadolinium enhancement. Whole-body CT revealed a mass lesion in the right submandibular gland, diffuse goiter, and bilateral hilar lymph node enlargement. Initially, IgG4-related disease was considered because of an elevated serum IgG4 level (240 mg/dl); however, biopsy of the submandibular gland showed non-caseating epithelioid cell granulomas that suggested sarcoidosis, which could be associated with the intracranial lesions causing his neurological manifestation. In cases of hypertrophic pachymeningitis, especially with increased serum IgG4 including our case, a careful assessment with pathological examination is critical for identifying various underlying conditions.