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: The presence of neuroinflammation and behavioral anomalies in mice lacking LAMP-2 expression highlights the importance of this lysosomal protein in brain. To assess whether loss of LAMP-2 leads to lysosomal dysfunction that correlates with the observed neuropathological abnormalities, we determined enzyme activities of the lysosomal hydrolases β-hexosaminidase and β-glucuronidase as well as the maturation of cathepsin D as a means of evaluating lysosomal function. Whereas a significant increase of all forms of cathepsin D (pro (p), immature (i) and mature (m)) was observed in the hippocampus and in the cortex (Figure 4a, Additional file 4), no marked change in the maturation of the enzyme was detected (Figure 4a). Additionally, the hippocampus of LAMP-2 knockout mice displayed a significant increase in β-hexosaminidase (Figure 4b) and β-glucuronidase (Figure 4c) activity whereas in the pons and cerebellum only β-hexosaminidase activity was elevated. In summary, among all other brain regions investigated, the hippocampus of LAMP-2-deficient mice showed the most consistent signs of alterations in lysosomal enzyme activity.Figure 4