Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion mutations in the ATXN2 gene, mainly affecting motor neurons in the spinal cord and Purkinje neurons in the cerebellum. While the large expansions were shown to cause SCA2, the intermediate length expansions lead to increased risk for several atrophic processes including amyotrophic lateral sclerosis and Parkinson variants, e.g. progressive supranuclear palsy. Intense efforts to pioneer a neuroprotective therapy for SCA2 require longitudinal monitoring of patients and identification of crucial molecular pathways. The ataxin-2 (ATXN2) protein is mainly involved in RNA translation control and regulation of nutrient metabolism during stress periods. The preferential mRNA targets of ATXN2 are yet to be determined. In order to understand the molecular disease mechanism throughout different prognostic stages, we generated an Atxn2-CAG100-knock-in (KIN) mouse model of SCA2 with intact murine ATXN2 expression regulation. Its characterization revealed somatic mosaicism of the expansion, with shortened lifespan, a progressive spatio-temporal pattern of pathology with subsequent phenotypes, and anomalies of brain metabolites such as N-acetylaspartate (NAA), all of which mirror faithfully the findings in SCA2 patients. Novel molecular analyses from stages before the onset of motor deficits revealed a strong selective effect of ATXN2 on Nat8l mRNA which encodes the enzyme responsible for NAA synthesis. This metabolite is a prominent energy store of the brain and a well-established marker for neuronal health. Overall, we present a novel authentic rodent model of SCA2, where in vivo magnetic resonance imaging was feasible to monitor progression and where the definition of earliest transcriptional abnormalities was possible. We believe that this model will not only reveal crucial insights regarding the pathomechanism of SCA2 and other ATXN2-associated disorders, but will also aid in developing gene-targeted therapies and disease prevention.

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism.

Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

Acute kidney injury in the elderly hospitalized patients.

OBJECTIVE: We aimed to evaluate acute kidney injury (AKI), occurrence of recovery and risk factors associated with permanent kidney injury and mortality in the elderly individuals. DESIGN: Evidence for this study was obtained from retrospective cohort study from our center. PATIENTS: A total of 193 patients (>65 years, mean age: 79.99 ± 6.93) with acute kidney injury were enrolled in this study between 2011 and 2012. PATIENTS with kidney failure or renal replacement therapy (RRT) history at admission were excluded. INTERVENTION: Main outcome measurements: serum creatinine (SCr), estimated GFR (with CKD-Epi) and complete blood counts were evaluated at baseline and daily basis thereafter. The AKI was defined based on Kidney Disease Improving Global Outcomes (KDIGO) classification. RESULTS: Among 193 patients, 43 (22%) patients required RRT. Mortality rate was 18% (n = 36) SCr levels were restored within 9.9 ± 6.7days on average (8-39 days). Sixteen patients (12.7%) required RRT after discharge. The mean hospital stay was 10.1 ± 8.6 days (7-41 days). Mortality rate of patients who have no renal recovery was higher (44.8% vs. 4.8%) than renal recovery group (p < 0.01). CONCLUSION: The AKI represents a frequent complication in the elderly patients with longer hospital stay and increased mortality and morbidity. Our results show that dialytic support requirement is an independent predictor of permeant kidney injury in the elderly AKI patients. Older age, low diastolic blood pressure, high CRP and low hemoglobin levels were independent risk factors for mortality.

Use of anti-Parkinson medication during pregnancy: a case series.

INTRODUCTION: Experience about the use and safety of anti-Parkinson (anti-PD) medication during pregnancy is scarce. METHODS: We have retrospectively evaluated the course and outcome of pregnancy in PD patients who used anti-PD medication during their pregnancy. RESULTS: 14 PD patients who used anti-PD medication during part or whole of their pregnancy were included. Dopamine agonists were used in 13 patients, levodopa/benserazide in 4, levodopa/carbidopa/entacapone in 1, rasagiline in 7, amantadine in 4, and biperiden in 1 patient. Nine patients were on combination treatment at the time of their pregnancy. During their whole pregnancy, dopamine agonists had been used in six patients, levodopa in four, and rasagiline in one. Four patients experienced adverse outcomes: one had spontaneous abortion while receiving pramipexole, one elderly mother gave birth to a child with Down syndrome, while receiving pramipexole and rasagiline, in one case, there was fetal distress under levodopa/benserazide, piribedil, and rasagiline which resolved spontaneously, in one case, one of the twins did not survive after the birth while the mother was receiving pramipexole and rasagiline. In none of these cases an association with the use of anti-PD medication and adverse outcomes was clearly established. In one patient, motor symptoms worsened despite high dose levodopa, four others experienced transient worsening upon dose reduction. CONCLUSION: Results in our case series suggest that levodopa, rasagiline, pramipexole, and ropinirole alone or in combination with each other may be considered relatively safe during pregnancy. Expected benefits and risks should be considered when prescribing anti-PD medication in pregnant women.