Ataxia with loss of Purkinje cells in a mouse model for Refsum disease

Ferdinandusse, Sacha; Zomer, Anna W.M.; Komen, J.C.; Brink, C.E. van den; Thanos, Melissa; Hamers, Frank P.T.; Wanders, Ronald J. A.; Saag, Paul T. van der; Poll-Thé, Bwee Tien; Brites, Pedro

doi:10.1073/pnas.0806066105

Cited by 100 publications

(76 citation statements)

References 27 publications

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“…In contrast, both the MPI 11Q/11Q and MPI 11Q/+ mice were indistinguishable from their WT littermates, even at 18 mo of age. We evaluated the gait patterns of 15-wk-old animals by using a CatWalk automated system (12). The footprints of the MPI 118Q/118Q mice revealed wobbling and a short-stepped gait (Fig.…”

Section: Resultsmentioning

confidence: 99%

Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6

Unno

Wakamori

Koike

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the Ca v 2.1 voltage-gated calcium channel. To elucidate how the expanded polyglutamine tract in this plasma membrane protein causes the disease, we created a unique knockin mouse model that modestly overexpressed the mutant transcripts under the control of an endogenous promoter (MPI-118Q). MPI-118Q mice faithfully recapitulated many features of SCA6, including selective Purkinje cell degeneration. Surprisingly, analysis of inclusion formation in the mutant Purkinje cells indicated the lysosomal localization of accumulated mutant Ca v 2.1 channels in the absence of autophagic response. The lack of cathepsin B, a major lysosomal cysteine proteinase, exacerbated the loss of Purkinje cells and was accompanied by an acceleration of inclusion formation in this model. Thus, the pathogenic mechanism of SCA6 involves the endolysosomal degradation pathway, and unique pathological features of this model further illustrate the pivotal role of protein context in the pathogenesis of polyglutamine diseases.

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Section: Resultsmentioning

confidence: 99%

Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6

Unno

Wakamori

Koike

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Postsurgical analgesia (1 mg/kg butorphanol s.c.) was performed twice a day for 3 days. Nerve conduction (WT, n = 6; shi, n = 4; Pex7-KO, n = 3; Pex7:shi DM, n = 4; Gnpat-KO, n = 5; Gnpat:shi DM, n = 3) was determined as previously described (44).…”

Section: Methodsmentioning

confidence: 99%

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Silva¹,

Eira²,

Lopes³

et al. 2014

J. Clin. Invest.

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111

117

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Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.

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“…The animals were allowed to traverse the walkway as many times as needed to obtain at least three smooth crossings (without stops or hesitations). 55 …”

Section: Behavioral Analysis Catwalkmentioning

confidence: 99%

Chronic Hyponatremia Causes Neurologic and Psychologic Impairments

Fujisawa

Sugimura

Takagi

et al. 2016

Journal of the American Society of Nephrology

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Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia may be linked to attention deficits, gait disturbances, risk of falls, and cognitive impairments. Such neurologic defects are associated with a reduction in quality of life and may be a significant cause of mortality. However, because underlying diseases such as adrenal insufficiency, heart failure, liver cirrhosis, and cancer may also affect brain function, the contribution of hyponatremia alone to neurologic manifestations and the underlying mechanisms remain unclear. Using a syndrome of inappropriate secretion of antidiuretic hormone rat model, we show here that sustained reduction of serum sodium ion concentration induced gait disturbances; facilitated the extinction of a contextual fear memory; caused cognitive impairment in a novel object recognition test; and impaired long-term potentiation at hippocampal CA3-CA1 synapses. In vivo microdialysis revealed an elevated extracellular glutamate concentration in the hippocampus of chronically hyponatremic rats. A sustained low extracellular sodium ion concentration also decreased glutamate uptake by primary astrocyte cultures, suggesting an underlying mechanism of impaired long-term potentiation. Furthermore, gait and memory performances of corrected hyponatremic rats were equivalent to those of control rats. Thus, these results suggest chronic hyponatremia in humans may cause gait disturbance and cognitive impairment, but these abnormalities are reversible and careful correction of this condition may improve quality of life and reduce mortality.

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Ataxia with loss of Purkinje cells in a mouse model for Refsum disease

Cited by 100 publications

References 27 publications

Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6

Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Chronic Hyponatremia Causes Neurologic and Psychologic Impairments

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