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Neurobiol Dis. 2018 Nov;119:65-78. doi: 10.1016/j.nbd.2018.07.013. Epub 2018 Jul 23.

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

Author information

1
Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, United States; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, United States. Electronic address: mcbridej@ohsu.edu.
2
Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, United States; Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, United States.
3
Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, United States; Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, United States; Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, United States.
4
Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, United States.
5
Advanced Imaging Research Center, Oregon Health and Science University, Portland, OR, United States.
6
Division of Comparative Medicine, Oregon National Primate Research Center, Beaverton, OR, United States.
7
Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, United States; Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, United States.

Abstract

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.

KEYWORDS:

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

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