The lysosomal polypeptide transporter TAPL is stabilized by the interaction with LAMP-1 and LAMP-2

Demirel, Özlem; Jan, Irina; Wolters, Dirk; Blanz, Judith; Säftig, Paul; Tampé, Robert; Abele, Rupert

doi:10.1242/jcs.087346

Cited by 40 publications

(45 citation statements)

References 40 publications

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“…21 If the autophagic-lysosomal dysfunction of neurons in AD results in exosomal uptake of lysosomal membrane proteins as well as lysosomal granule cathepsin D, we hypothesized that LAMP-1 levels are elevated in neurally derived plasma exosomes from patients with AD as contrasted with those from AC controls. Exosomal levels of LAMP-1 for the patients with AD in cross-sectional studies were 1,808 6 204 pg/mL (mean 6 SEM), which were significantly higher than the level of 946 6 119 pg/mL for the control AC participants (p 5 0.00051) (figure 1).…”

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confidence: 99%

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease

et al. 2015

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Objective: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy.Methods: Blood exosomes obtained once from patients with AD (n 5 26) or frontotemporal dementia (n 5 16), other patients with AD (n 5 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker.Results: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p # 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p # 0.006).Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p # 0.0003).Conclusions: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies. There is an urgent need for biomarkers that accurately detect pathogenic components of Alzheimer disease (AD) before appearance of neurologic signs. Early treatments directed to such targets could limit or reverse neuronal damage and prevent development of overt AD. Recent analyses of neurally derived plasma exosomal proteins have shown significantly higher levels of the pathogenic proteins P-T181-tau, P-S396-tau, and b-amyloid (Ab)1-42 in AD than in case controls.1 Discriminant modeling of these exosomal protein levels correctly classified more than 96% of patients with AD. Neurally derived plasma exosomal levels of P-T181-tau, P-S396-tau, and Ab1-42 also were significantly higher in preclinical AD than for controls up to 10 years before appearance of neurologic signs. Altered levels of phosphorylated forms of the insulin receptor proximal signaling protein, termed insulin receptor substrate (IRS), in neurally derived plasma exosomes supported the

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confidence: 99%

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease

et al. 2015

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“…The presence of LAMP-2 on the inner surface of lysosome membranes might also help to maintain an acidic environment in the lysosome and prevent lysosomal digestive enzymes from auto-digesting cellular cytoplasmic components (Endo et al, 2015;Saftig et al, 2001). Interestingly, through its cytoplasmic tail, LAMP-2B (but not LAMP-2A) has been found to interact with the transporter associated with antigen processing like (TAPL; also known as ABCB9) protein, which transports peptides in the cytosol to the lysosomal lumen (Demirel et al, 2012). Although this interaction does not appear to affect the subcellular localization or transportation of the peptides, LAMP-2B might instead act to increase the half-life of TAPL (Demirel et al, 2012).…”

Section: Autophagymentioning

confidence: 99%

“…Interestingly, through its cytoplasmic tail, LAMP-2B (but not LAMP-2A) has been found to interact with the transporter associated with antigen processing like (TAPL; also known as ABCB9) protein, which transports peptides in the cytosol to the lysosomal lumen (Demirel et al, 2012). Although this interaction does not appear to affect the subcellular localization or transportation of the peptides, LAMP-2B might instead act to increase the half-life of TAPL (Demirel et al, 2012). Other major players in the fusion of autophagosomes to lysosomes are the soluble NSF attachment protein receptor (SNARE) proteins; these are not known to interact with LAMP-2.…”

Section: Autophagymentioning

confidence: 99%

Danon disease – dysregulation of autophagy in a multisystem disorder with cardiomyopathy

Rowland

Sweet

Mestroni

et al. 2016

Journal of Cell Science

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Danon disease is a rare, severe X-linked form of cardiomyopathy caused by deficiency of lysosome-associated membrane protein 2 (LAMP-2). Other clinical manifestations include skeletal myopathy, cognitive defects and visual problems. Although individuals with Danon disease have been clinically described since the early 1980s, the underlying molecular mechanisms involved in pathological progression remain poorly understood. LAMP-2 is known to be involved in autophagy, and a characteristic accumulation of autophagic vacuoles in the affected tissues further supports the idea that autophagy is disrupted in this disease. The LAMP2 gene is alternatively spliced to form three splice isoforms, which are thought to play different autophagy-related cellular roles. This Commentary explores findings from genetic, histological, functional and tissue expression studies that suggest that the specific loss of the LAMP-2B isoform, which is likely to be involved in macroautophagy, plays a crucial role in causing the Danon phenotype. We also compare findings from mouse and cellular models, which have allowed for further molecular characterization but have also shown phenotypic differences that warrant attention. Overall, there is a need to better functionally characterize the LAMP-2B isoform in order to rationally explore more effective therapeutic options for individuals with Danon disease.

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“…LAMP2's three protein products (LAMP2-A, LAMP2-B, and LAMP2-C) are integral membrane proteins, sharing a common N-terminal (luminal) domain, but with distinct transmembrane domains and cytoplasmic tails. These proteins permit the targeted import of cytoplasmic proteins (LAMP2-A, LAMP2-B) and RNA (LAMP2-C) into lysosomes for degradation (Cuervo and Dice 1996;Bandyopadhyay et al 2008;Kaushik et al 2011;Demirel et al 2012;Fujiwara et al 2013). The majority of reported Danon disease alleles are private, with nonsense and frameshift mutations predominating (Boucek et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Danon Disease Due to a Novel LAMP2 Microduplication

et al. 2013

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Danon disease is a rare X-linked disorder comprising hypertrophic cardiomyopathy, skeletal myopathy, intellectual disability, and retinopathy; mutations of the lysosome-associated membrane protein gene LAMP2 are responsible. Most affected persons exhibit "private" point mutations; small locus rearrangements have recently been reported in four cases. Here, we describe the clinical, pathologic, and molecular features of a male proband and his affected mother with Danon disease and a small LAMP2 microduplication. The proband presented at age 12 years with exercise intolerance, hypertrophic cardiomyopathy, and increased creatine kinase. Endomyocardial biopsy findings were nonspecific, showing myocyte hypertrophy and reactive mitochondrial changes. Quadriceps muscle biopsy demonstrated the characteristic autophagic vacuoles with sarcolemma-like features. LAMP2 tissue immunostaining was absent; however, LAMP2 sequencing was normal.

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The lysosomal polypeptide transporter TAPL is stabilized by the interaction with LAMP-1 and LAMP-2

Cited by 40 publications

References 40 publications

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease

Danon disease – dysregulation of autophagy in a multisystem disorder with cardiomyopathy

Danon Disease Due to a Novel LAMP2 Microduplication

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