Discovery of a CLN7 model of Batten disease in non-human primates

NEUROBIOLOGY OF DISEASE

卷:119

Article

McBride, Jodi L.^1,2  Neuringer, Martha^1,4  Ferguson, Betsy^1,3,5  Kohama, Steven G.¹  Tagge, Ian J.⁶  Zweig, Robert C.⁷  Renner, Laurie M.¹  McGill, Trevor J.^1,4  Stoddard, Jonathan¹  Peterson, Samuel¹  Su, Weiping¹  Sherman, Larry S.^1,8  Domire, Jacqueline S.¹  Ducore, Rebecca M.⁷  Colgin, Lois M.⁷  Lewis, Anne D.⁷ 

[1] Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR USA

[2] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA

[3] Oregon Natl Primate Res Ctr, Div Genet, Beaverton, OR USA

[4] Oregon Hlth & Sci Univ, Dept Ophthalmol, Casey Eye Inst, Portland, OR 97201 USA

[5] Oregon Hlth & Sci Univ, Mol & Med Genet, Portland, OR 97201 USA

[6] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97201 USA

[7] Oregon Natl Primate Res Ctr, Div Comparat Med, Beaverton, OR USA

[8] Oregon Hlth & Sci Univ, Dept Cell Dev & Canc Biol, Portland, OR 97201 USA

关键词: CLN7;    MFSD8;    Late infantile neuronal ceroid lipofuscinosis;    Batten disease;    Non-human primate;    Neurodegeneration;    Retinal degeneration;    Lysosomal storage disease;    Japanese macaque;    Large animal model;   

DOI  :  10.1016/j.nbd.2018.07.013

来源: Elsevier

【 摘 要 】

We have identified a natural Japanese macaque model of the childhood neurodegenerative disorder neuronal ceroid lipofuscinosis, commonly known as Batten Disease, caused by a homozygous frameshift mutation in the CLN7 gene (CLN7(-/-)). Affected macaques display progressive neurological deficits including visual impairment, tremor, incoordination, ataxia and impaired balance. Imaging, functional and pathological studies revealed that CLN7(-/-) macaques have reduced retinal thickness and retinal function early in disease, followed by profound cerebral and cerebellar atrophy that progresses over a five to six-year disease course. Histological analyses showed an accumulation of cerebral, cerebellar and cardiac storage material as well as degeneration of neurons, white matter fragmentation and reactive gliosis throughout the brain of affected animals. This novel CLN7(-/-) macaque model recapitulates key behavioral and neuropathological features of human Batten Disease and provides novel insights into the pathophysiology linked to CLN7 mutations. These animals will be invaluable for evaluating promising therapeutic strategies for this devastating disease.

【 授权许可】

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