Abstract
To test the hypothesis that the cerebrospinal fluid (CSF) could provide a spreading route for pathogenesis of amyotrophic lateral sclerosis (ALS), we have examined the effects of intraventricular infusion during 2 weeks of pooled CSF samples from sporadic ALS patients or control CSF samples into transgenic mice expressing human TDP43WT which do not develop pathological phenotypes. Infusion of ALS-CSF, but not of control CSF, triggered motor and cognitive dysfunction, as well as ALS-like pathological changes including TDP43 proteinopathy, neurofilament disorganization and neuroinflammation. In addition, the neuron-specific translational profiles from peptide analyses of immunoprecipitated ribosomes revealed dysregulation of multiple protein networks in response to ALS-CSF altering cytoskeletal organization, vesicle trafficking, mitochondrial function, and cell metabolism. With normal mice, similar ALS-CSF infusion induced mild motor dysfunction but without significant TDP43 pathology in spinal neurons. We conclude that the CSF from sporadic ALS contains factors that can transmit and disseminate disease including TDP43 proteinopathy into appropriate recipient animal model expressing human TDP43. These findings open new research avenues for the discovery of etiogenic factors for sporadic ALS and for the testing of drugs aiming to neutralize the ALS-CSF toxicity.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is characterized by relentlessly progressive degeneration of motor pathways and severe muscular atrophy; with a mean survival rate of 3–5 years following onset
Exposure to ALS-cerebrospinal fluid (CSF) induced NF-κB activation and TAR DNA Binding protein 43 (TDP43) mislocalization in-vitro and in-vivo We studied the effect of ALS-CSF samples pooled from 7 males and 3 female ALS subjects after obtaining informed consent
We studied the effects of pooled CSF samples on NFκB activity and on cytoplasmic mislocalization of TDP43 using NSC-34 cells stably transfected with vectors expressing human TDP43WT and NF-κB-p65-luciferase reporter gene (NSC-34-hTDP43WT-HA-luc p65) capable of expressing luciferase upon NF-κB-p65 activation [49]
Summary
Amyotrophic Lateral Sclerosis (ALS) is characterized by relentlessly progressive degeneration of motor pathways and severe muscular atrophy; with a mean survival rate of 3–5 years following onset. The incidence of amyotrophic lateral sclerosis is 1 to 3 per 100,000 person/year with a peak age of onset being 58–63 years for the sporadic variant and 47–52 years for the familial cases [35, 48]. Pathological hallmarks of ALS include motor neuronal death, muscle atrophy, as well as severe, chronic neuroinflammation and glial involvement. In familial cases of ALS, mutations in several genes have been implicated including SOD1, C9ORF72, ATXN2, OPTN, VCP, VAPB, DCTN1, Fig. 4, UBQLN2, SQSTM1 and TARDBP encoding TAR DNA Binding protein 43 (TDP43) [8]. Various environmental factors, including physical insults and injury, nutrition, smoking and ethnicity have been proposed but no single factor has been sufficient to explain the pathogenesis of sALS [10, 18, 33]
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