A reversal learning task detects cognitive deficits in a Dachshund model of late-infantile neuronal ceroid lipofuscinosis

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive lysosomal storage diseases characterized by progressive neurodegeneration and by accumulation of autofluorescent storage material in the central nervous system and other tissues. One of the most prominent clinical signs of NCL is progressive decline in cognitive function. We previously described a frame shift mutation of TPP1 in miniature long-haired Dachshunds which causes an early-onset form of NCL analogous to classical late-infantile onset NCL (CLN2) in children. Dogs homozygous for the TPP1 mutation exhibit progressive neurological signs similar to those exhibited by human patients. In order to establish biomarkers for evaluating the efficacy of ongoing therapeutic studies in this canine model, we characterized phenotypic changes in 13 dogs through 9 months of age. Cognitive function was assessed using a T-maze reversal learning task. Cognitive dysfunction was detected in affected dogs as early as 6 months of age and worsened as the disease progressed. Physical and neurological examination, funduscopy, and electroretinography (ERG) were performed at regular intervals. Only changes in ERG responses revealed signs of disease progression earlier than the reversal learning task. In the later stages of the disease clinical signs of visual and motor deficits became evident. The visual and motor deficits were not severe enough to affect the performance of dogs in the T-maze. Declining performance on the reversal learning task is a sensitive measure of higher order cognitive dysfunction which can serve as a useful biomarker of disease progression.

AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease

“…The TPP1-null dachshund disease model has a frameshift mutation in TPP1 (17) with no detectable TPP1 protein or activity in blood or tissues and progressive neurodegenerative symptomatology that recapitulates human TPP1 deficiency (18, 19). First, we tested whether rAAV transduction of ependyma with TPP1 can provide widespread access of recombinant TPP1 to the central nervous system.…”

Aging in the Canine and Feline Brain

“…84 This model system is particularly interesting because intrathecal administration of TTP1 results in decreased lysosomal storage. 85 It is likely that a better understanding of how mitochondrial dysfunction and neuronal loss develop in the NCLs, as well as how they may be reversed with therapy, will shed light on similar mechanisms postulated to occur in brain aging.…”

Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis

“…Affected animals display progressive neurological decline requiring euthanasia at 10-11 months old [15,26]. We have previously demonstrated that repeat intrathecal (IT) injection results in brain distribution of active rhTPP1 and reduced accumulation of lysosomal storage [32].…”