Abstract
Canavan Disease (CD) is a leukodystrophy caused by homozygous null mutations in the gene encoding aspartoacylase (ASPA). ASPA-deficiency is characterized by severe psychomotor retardation, and excessive levels of the ASPA substrate N-acetylaspartate (NAA). ASPA is an oligodendrocyte marker and it is believed that CD has a central etiology. However, ASPA is also expressed by Schwann cells and ASPA-deficiency in the periphery might therefore contribute to the complex CD pathology. In this study, we assessed peripheral and central auditory function in the AspalacZ/lacZ rodent model of CD using auditory brainstem response (ABR). Increased ABR thresholds and the virtual loss of waveform peaks 4 and 5 from AspalacZ/lacZ mice, indicated altered central auditory processing in mutant mice compared with Aspawt/wt controls and altered central auditory processing. Analysis of ABR latencies recorded from AspalacZ/lacZ mice revealed that the speed of nerve conduction was unchanged in the peripheral part of the auditory pathway, and impaired in the CNS. Histological analyses confirmed that ASPA was expressed in oligodendrocytes and Schwann cells of the auditory system. In keeping with our physiological results, the cellular organization of the cochlea, including the organ of Corti, was preserved and the spiral ganglion nerve fibres were normal in ASPA-deficient mice. In contrast, we detected substantial hypomyelination in the central auditory system of AspalacZ/lacZ mice. In summary, our data suggest that the lack of ASPA in the CNS is responsible for the observed hearing deficits, while ASPA-deficiency in the cochlear nerve fibres is tolerated both morphologically and functionally.
Highlights
The lack of the enzyme aspartoacylase (ASPA) causes the fatal leukodystrophy Canavan disease (CD) [1]
The loss of auditory brainstem response (ABR) peaks was even more pronounced in aged mutants. 4/4 of the 9month-old mutant mice showed no peak 4 (P4) or P5 compared with 4/4 age-matched controls showing all 5 peaks (Figure S1A, B)
We have identified deficits in hearing sensitivity and signaling in AspalacZ/lacZ mice as a novel facet in the complex pathology of CD
Summary
The lack of the enzyme aspartoacylase (ASPA) causes the fatal leukodystrophy Canavan disease (CD) [1]. In the absence of ASPA, its substrate N-acetyl-aspartate (NAA) can no longer be metabolized into acetate and L-aspartate resulting in a diagnostically relevant increase in NAA in the brain and urine of CD patients. Elevated NAA is believed to underlie the widespread vacuolization that was initially described as spongiform degeneration of the brain [2]. CD patients, even with the same Aspa mutation, have a life expectancy between 6 months through to the third decade [3]. The clinical heterogeneity is replicated in different mouse models of CD with various longevity and disease severity [4,5,6]. While homozygous null-mutations in the Aspa gene are the key-unifying feature in CD, genotype-tophenotype correlations have proven difficult, suggesting the influence of genetic modifiers [5,7]
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