LAMP-2 deficiency leads to hippocampal dysfunction but normal clearance of neuronal substrates of chaperone-mediated autophagy in a mouse model for Danon disease.
Bottom Line: Intellectual dysfunction observed in the human disease suggests a pivotal role of LAMP-2 within brain.The absence of LAMP-2 in murine brain led to inflammation and abnormal behavior, including motor deficits and impaired learning.The absence of LAMP-2 did not apparently affect MA or steady-state levels of selected CMA substrates in brain or neuroblastoma cells under physiological and prolonged starvation conditions.
The Lysosomal Associated Membrane Protein type-2 (LAMP-2) is an abundant lysosomal membrane protein with an important role in immunity, macroautophagy (MA) and chaperone-mediated autophagy (CMA). Mutations within the Lamp2 gene cause Danon disease, an X-linked lysosomal storage disorder characterized by (cardio)myopathy and intellectual dysfunction. The pathological hallmark of this disease is an accumulation of glycogen and autophagic vacuoles in cardiac and skeletal muscle that, along with the myopathy, is also present in LAMP-2-deficient mice. Intellectual dysfunction observed in the human disease suggests a pivotal role of LAMP-2 within brain. LAMP-2A, one specific LAMP-2 isoform, was proposed to be important for the lysosomal degradation of selective proteins involved in neurodegenerative diseases such as Huntington's and Parkinson's disease. To elucidate the neuronal function of LAMP-2 we analyzed knockout mice for neuropathological changes, MA and steady-state levels of CMA substrates. The absence of LAMP-2 in murine brain led to inflammation and abnormal behavior, including motor deficits and impaired learning. The latter abnormality points to hippocampal dysfunction caused by altered lysosomal activity, distinct accumulation of p62-positive aggregates, autophagic vacuoles and lipid storage within hippocampal neurons and their presynaptic terminals. The absence of LAMP-2 did not apparently affect MA or steady-state levels of selected CMA substrates in brain or neuroblastoma cells under physiological and prolonged starvation conditions. Our data contribute to the understanding of intellectual dysfunction observed in Danon disease patients and highlight the role of LAMP-2 within the central nervous system, particularly the hippocampus.
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Mentions: Danon disease patients present with neurological manifestations in the form of intellectual dysfunction [25-27]. LAMP-2-deficient mice were subjected to a battery of behavioral tests that included measures of motor performance (gait analysis, grip strength, activity, rotarod and swim test) and exploration as well as indices of learning and memory (Y-maze, contextual fear conditioning). Gross motor behavior appeared unaltered in LAMP-2-deficient mice, as there were no significant differences when compared to wild-type controls in grip strength, rotarod performance and home cage activity (Additional file 3a-c). Likewise, rudimentary gait parameters such as base-widths and stride lengths were similar between genotypes (data not shown). However, maximal paw area was reduced in LAMP-2-deficient mice (Figure 3a). Although this might indicate altered plantar placing in the context of a motor deficit, it is more likely a consequence of reduced body weight in these mice (data not shown). Impaired motor performance of LAMP-2-deficient mice was evident in the swim test exemplified by severely reduced swimming velocity (Figure 3b). This effect was not confirmed to be caused by muscular weakness as grip strength performance was normal. Reduced exploratory activity was observed in the exploration test (Figure 3c). Considering unaltered levels of home cage activity (Additional file 3c), this effect does not appear to reflect general hypolocomotion of LAMP-2-deficient mice. Rather, it could indicate blunted affective response to the novel environment. LAMP-2-deficient mice show an increased freezing percentage during the habituation phase of the contextual fear conditioning experiment, which may be the consequence of reduced exploratory movement. However, fear conditioning as well as contextual and cued fear memory was intact in LAMP-2-deficient mice (Figure 3d). In the Y-maze task, LAMP-2-deficient mice made relatively less alternations (Figure 3e) in comparison with wild-type control mice, indicating impaired working memory. In conclusion, LAMP-2-deficient mice show particular motor impairments, reduced exploratory activity and signs of impaired memory, consistent with hippocampal dysfunction.Figure 3