De novo FUS P525L mutation in Juvenile amyotrophic lateral sclerosis with dysphonia and diplopia.

Juvenile amyotrophic lateral sclerosis (jALS) is characterized by progressive upper and lower motor neuron degeneration leading to facial muscle spasticity, spastic dysarthria, and spastic gait with an early onset (before 25 years old). Unlike adult-onset amyotrophic lateral sclerosis (ALS), patients with jALS tend to have slower progression of motor neuron disease and prolonged survival to a normal life expectancy. Mutations in FUS gene have been reported in jALS,(1) including p.P525L mutation that has been consistently associated with early onset and aggressive presentation.(2) Here, we report a patient carrying p.P525L FUS mutation and experiencing an aggressive course of ALS presenting with dysphonia and diplopia.

A novel mutation in the CSF1R gene causes a variable leukoencephalopathy with spheroids.

Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids is a neurodegenerative disease associated with mutations in the colony-stimulating factor 1 receptor gene (CSF1R). A 44-year-old woman with a 7-year history of depression presented with neurological signs and a recent cognitive decline. The diagnosis of hereditary diffuse leukoencephalopathy with neuroaxonal spheroids was suspected based on the findings of a predominant frontal leukoencephalopathy and neuroaxonal spheroids on brain biopsy. She shares with her mother a novel CSF1R exon 18 missense mutation (c.2350G > A; p.V784M). The mother has a long-standing bipolar disorder and mild multifocal white matter abnormalities in her 70s. This is the first report of hereditary diffuse leukoencephalopathy with neuroaxonal spheroids due to this novel CSF1R missense mutation. Our report suggests that either marked intrafamilial variability or incomplete penetrance can be associated with CSF1R mutations. The observation of a small bone cyst in our patient supports the hypothesis that hereditary diffuse leukoencephalopathy with neuroaxonal spheroids and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy may belong to a spectrum of overlapping phenotypes.

Stress differentially regulates the effects of voluntary exercise on cell proliferation in the dentate gyrus of mice.

It has been well-established that cell proliferation and neurogenesis in the adult mouse dentate gyrus (DG) can be regulated by voluntary exercise. Recent evidence has suggested that the effects of voluntary exercise can in turn be influenced by environmental factors that regulate the amount of stress an animal is exposed to. In this study, we use bromodeoxyuridine and proliferating cell nuclear antigen immunohistochemistry to show that voluntary exercise produces a significant increase in cell proliferation in the adult mouse DG in both isolated and socially housed mice. This effect on proliferation translates into an increase in neurogenesis and neuronal branching of new neurons in the mice that exercised. Although social condition did not regulate proliferation in young adult mice, an effect of social housing could be observed in mice exposed to acute restraint stress. Surprisingly, only exercising mice housed in isolated conditions showed an increase in cellular proliferation following restraint stress, whereas socially housed, exercising mice, failed to show a significant increase in proliferation. These findings indicate that social housing may increase the effects of any stressful episodes on hippocampal neurogenesis in the mouse DG.

Hippocampal cell proliferation is reduced following prenatal ethanol exposure but can be rescued with voluntary exercise.

The ingestion of ethanol during pregnancy has a number of deleterious consequences for the unborn offspring, producing structural and functional deficits that affect the brain and many other organs into adulthood. The hippocampus is a brain area that is particularly sensitive to ethanol's adverse effects. In a previous study we showed that voluntary exercise can ameliorate deficits in long-term potentiation and behavior that occur following prenatal ethanol exposure (Eur J Neurosci, 2005, 21, 1719-1726). In the present study, we investigated the effects of prenatal ethanol exposure on neurogenesis in adulthood, and tested the hypothesis that voluntary exercise would ameliorate any deficits observed. Sprague-Dawley females were administered one of three diets throughout gestation: (i) ethanol (E), a liquid diet containing 36.5% ethanol-derived calories; (ii) pair-fed (PF), a liquid control diet, with maltose-dextrin isocalorically substituted for ethanol, in the amount consumed by an E partner (g/kg body wt/day of gestation); and (iii) ad-libitum-fed control (C), normal laboratory chow and water, ad libitum. The offspring were housed individually at postnatal day (PND) 35, and at PND 50 were randomly assigned to cages either with or without an exercise wheel. BrdU (200 mg/kg, I.P.) was injected on PND 57, and animals terminated either 24 h (proliferation) or 4 weeks (neurogenesis) later. Our results demonstrate that prenatal ethanol exposure significantly decreases both cell proliferation and neurogenesis in the adult dentate gyrus. Animals in the PF condition also showed reduced neurogenesis. In contrast, all animals that engaged in voluntary exercise showed a significant increase in cell proliferation and neurogenesis. These results indicate that prenatal ethanol exposure can suppress both cell proliferation and neurogenesis, and that these effects may be, at least in part, nutritionally mediated. Importantly, voluntary exercise appears to have beneficial effects for these long-lasting deficits in hippocampal volume and cell number that have been observed in animals exposed to ethanol in utero.

Voluntary exercise rescues deficits in spatial memory and long-term potentiation in prenatal ethanol-exposed male rats.

Prenatal ethanol exposure can lead to long-lasting impairments in the ability to process spatial information in rats, as well as produce long-lasting deficits in the ability of animals to exhibit long-term potentiation, a biological model of learning and memory processing. Conversely, we have recently shown that both spatial memory and long-term potentiation can be enhanced in animals that are given access to a running wheel in their home cage. In the present study, Sprague-Dawley rat dams were given one of three diets throughout gestation: (i) a liquid diet containing ethanol (35.5% ethanol-derived calories); (ii) a liquid diet, isocaloric to the ethanol diet, but with maltose-dextrin substituting for the ethanol derived calories and (iii) an ad libitum diet of standard rat chow. At weaning (28 days) animals were housed individually in either a standard rat cage, or a cage that contained a running wheel. Adult offspring were tested on a two trial version of the Morris water maze beginning at postnatal day 60, for five consecutive days. Following this, the capacity of the perforant path to dentate gyrus pathway to sustain long-term potentiation was examined in these animals using theta-patterned conditioning stimuli. Our results demonstrate that prenatal ethanol exposure can produce pronounced deficits in both spatial memory and long-term potentiation, but that allowing animal's access to voluntary exercise can attenuate these deficits to the point that those exposed to ethanol prenatally can no longer be differentiated from control animals. These findings indicate that voluntary exercise may have therapeutic benefits for individuals that have undergone prenatal ethanol exposure.