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.
Highlights
The neuronal ceroid lipofuscinoses (NCLs) are a group of heterogenic, fatal childhood neurodegenerative diseases caused by mutations in 13 different genes described to date (CLN1-CLN14; the mutation for CLN9 has yet to be identified) (Kousi et al, 2012)
We have identified a cohort of ten consanguineous Japanese macaques at the Oregon National Primate Research Center (ONPRC) bearing a haplotype that includes a frameshift mutation within exon 8 of the CLN7 gene (CLN7−/−))
Five Japanese macaque clinical cases, designated BD1, BD2, BD3, BD5 and BD6 presented at the ONPRC between 4 and 5 years of age with a relatively homogeneous and progressive constellation of neurologic symptoms including incoordination, hindlimb weakness, head tilt, intention tremor, ataxia, hypermetria and impaired balance (Table 1)
Summary
The neuronal ceroid lipofuscinoses (NCLs) are a group of heterogenic, fatal childhood neurodegenerative diseases caused by mutations in 13 different genes described to date (CLN1-CLN14; the mutation for CLN9 has yet to be identified) (Kousi et al, 2012). The constellation of neuropathological and behavioral manifestations of the NCLs are surprisingly similar, characterized by the accumulation of abundant intracytoplasmic, autofluorescent lipopigment throughout the central nervous system (CNS), neuronal degeneration and associated neuroinflammation (Anderson et al, 2013; Cooper et al, 2015; Palmer et al, 2013; Radke et al, 2015). The NCLs are fatal and treatments for the NCLs remain largely palliative, an enzyme replacement strategy delivering cerliponase alpha (BrineuraTM) to treat the motor decline associated with the CLN2 form of NCL was recently approved by the Food and Drug Administration in April of 2017
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