Autophagy in major human diseases

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders

LAMP-2: a control step for phagosome and autophagosome maturation

The two structurally related, major lysosomal membrane proteins LAMP-1 and LAMP-2 were for a long time regarded as crucial for the protection of the lysosomal membrane from the hostile lumenal environment. However, recent studies on the effects of single and combined LAMP-deficiency in mice reveal alternative functions. LAMP proteins, but especially LAMP-2, are important regulators in successful maturation of both autophagosomes and phagosomes. LAMP-2 deficiency causes an accumulation of autophagosomes in many tissues leading to cardiomyopathy and myopathy in mice and patients suffering from Danon Disease. The central role of LAMP-2 is also underlined by a recent study where LAMP-2 knockout mice are shown to have an impaired phagosomal maturation in neutrophils. The impairment of this important innate immune defense process in these mice leads to periodontitis, one of the most widespread infectious diseases worldwide. The retarded clearance of bacterial pathogens was probably due to an inefficient fusion capacity between lysosomes and phagosomes. Recent studies in LAMP double-knockout fibroblasts suggests that LAMP-deficiency impairs the dynein-mediated transport of lysosomes to perinuclear regions where fusion with (auto)phagosomes occurs. Addendum to: Beertsen W, Willenborg M, Everts V, Zirogianni A, Podschun R, Schroder B, Eskelinen EL, Saftig P. Impaired phagosomal maturation in neutrophils leads to periodontitis in lysosomal- associated membrane protein-2 knockout mice. J Immunol 2008; 180:475-82

Impaired phagosomal maturation in neutrophils leads to periodontitis in lysosomal-associated membrane protein-2 knockout mice

Inflammatory periodontal diseases constitute one of the most common infections in humans, resulting in the destruction of the supporting structures of the dentition. Circulating neutrophils are an essential component of the human innate immune system. We observed that mice deficient for the major lysosomal-associated membrane protein-2 (LAMP-2) developed severe periodontitis early in life. This development was accompanied by a massive accumulation of bacterial plaque along the tooth surfaces, gingival inflammation, alveolar bone resorption, loss of connective tissue fiber attachment, apical migration of junctional epithelium, and pathological movement of the molars. The inflammatory lesions were dominated by polymorphonuclear leukocytes (PMNs) apparently being unable to efficiently clear bacterial pathogens. Systemic treatment of LAMP-2-deficient mice with antibiotics prevented the periodontal pathology. Isolated PMNs from LAMP-2-deficient mice showed an accumulation of autophagic vacuoles and a reduced bacterial killing capacity. Oxidative burst response was not altered in these cells. Latex bead and bacterial feeding experiments showed a reduced ability of the phagosomes to acquire an acidic pH and late endocytic markers, suggesting an impaired fusion of late endosomes-lysosomes with phagosomes. This study underlines the importance of LAMP-2 for the maturation of phagosomes in PMNs. It also underscores the requirement of lysosomal fusion events to provide sufficient antimicrobial activity in PMNs, which is needed to prevent periodontal disease