From clues to mechanisms - Understanding ALS initiation and spread

Baystate Medical Center/Tufts University School of Medicine, 759 Chestnut Street, S4648, Springfield, MA 01199 .
Neurology (Impact Factor: 8.3). 10/2008; 71(12):872-3. DOI: 10.1212/01.wnl.0000325992.50108.60
Source: PubMed
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    ABSTRACT: OBJECTIVES: To examine whether there is a continued increase in neurological deaths in the major developed countries over the period 1979-2010. STUDY DESIGN: Analyzes changing patterns of neurological deaths and Total Mortality of people aged 55-74 years by sex. METHODS: Baseline WHO 3-year average mortality for 1979-81 were compared with changes in 2008-10, for Total Mortality and the neurological categories Nervous Disease, and Alzheimer & other Dementias deaths in rates per million. To control for different diagnostic practice, the focus is upon Total Neurological Deaths in relation to Total Mortality and Odds ratios are calculated. UK Motor Neuron Disease, Parkinson's disease and variant CJD are explored as possible constituent categories of Nervous Disease for other countries. RESULTS: Total Mortality fell substantially in every country, conversely, Nervous Disease and Alzheimer's rose in seven and six countries respectively. Total Neurological Deaths for males and females increased significantly in Australia, Canada, England & Wales, Italy, the Netherlands and especially the USA. Unlike motor neurone disease, variant CJD' deaths in England and Wales did not contribute substantially to the overall neurological increases found. Odds ratios indicated that neurological deaths differentially increased significantly in every country compared to Total Mortality. CONCLUSIONS: These results pose a major public health problem, as the epigenetic contribution to these changes, rather than longevity, have serious implications indicating earlier onset of neurological morbidity pressurizing families, health and social care services, with resource implications especially for Australia, Canada, Italy, Netherlands, Spain, the UK and the USA.
    Public health 04/2013; 127(4). DOI:10.1016/j.puhe.2012.12.018 · 1.26 Impact Factor
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    ABSTRACT: OBJECTIVE: To determine, when, how, and which neurons initiate the onset of pathophysiology in amyotrophic lateral sclerosis (ALS) using a transgenic mutant sod1 zebrafish model and identify neuroprotective drugs. METHODS: Proteinopathies such as ALS involve mutant proteins that misfold and activate the heat shock stress response (HSR). The HSR is indicative of neuronal stress, and we used a fluorescent hsp70-DsRed reporter in our transgenic zebrafish to track neuronal stress and to measure functional changes in neurons and muscle over the course of the disease. RESULTS: We show that mutant sod1 fish first exhibited the HSR in glycinergic interneurons at 24 hours postfertilization (hpf). By 96 hpf, we observed a significant reduction in spontaneous glycinergic currents induced in spinal motor neurons. The loss of inhibition was followed by increased stress in the motor neurons of symptomatic adults and concurrent morphological changes at the neuromuscular junction (NMJ) indicative of denervation. Riluzole, the only approved ALS drug and apomorphine, an NRF2 activator, reduced the observed early neuronal stress response. INTERPRETATION: The earliest event in the pathophysiology of ALS in the mutant sod1 zebrafish model involves neuronal stress in inhibitory interneurons, resulting from mutant Sod1 expression. This is followed by a reduction in inhibitory input to motor neurons. The loss of inhibitory input may contribute to the later development of neuronal stress in motor neurons and concurrent inability to maintain the NMJ. Riluzole, the approved drug for use in ALS, modulates neuronal stress in interneurons, indicating a novel mechanism of riluzole action. ANN NEUROL 2011.
    Annals of Neurology 02/2013; 73(2). DOI:10.1002/ana.23780 · 11.91 Impact Factor
  • Journal of Neuropathology and Experimental Neurology 01/2011; 70(1):97-8; author reply 98-100. DOI:10.1097/01.JNEN.0000392910.86750.32 · 4.37 Impact Factor