Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline.

Age-related declines in cognitive fitness are associated with a reduction in autophagy, an intracellular lysosomal catabolic process that regulates protein homeostasis and organelle turnover. However, the functional significance of autophagy in regulating cognitive function and its decline during aging remains largely elusive. Here, we show that stimulating memory upregulates autophagy in the hippocampus. Using hippocampal injections of genetic and pharmacological modulators of autophagy, we find that inducing autophagy in hippocampal neurons is required to form novel memory by promoting activity-dependent structural and functional synaptic plasticity, including dendritic spine formation, neuronal facilitation, and long-term potentiation. We show that hippocampal autophagy activity is reduced during aging and that restoring its levels is sufficient to reverse age-related memory deficits. Moreover, we demonstrate that systemic administration of young plasma into aged mice rejuvenates memory in an autophagy-dependent manner, suggesting a prominent role for autophagy to favor the communication between systemic factors and neurons in fostering cognition. Among these youthful factors, we identify osteocalcin, a bone-derived molecule, as a direct hormonal inducer of hippocampal autophagy. Our results reveal that inducing autophagy in hippocampal neurons is a necessary mechanism to enhance the integration of novel stimulations of memory and to promote the influence of systemic factors on cognitive fitness. We also demonstrate the potential therapeutic benefits of modulating autophagy in the aged brain to counteract age-related cognitive impairments.

Autophagy in Natural History and After ERT in Glycogenosis Type II.

We studied the role of autophagy in a series of 10 infantile-, juvenile-, and adult-onset GSDII patients and investigated autophagy blockade in successive biopsies of adult cases during disease natural history. We also correlated the autophagosome accumulation and efficiency of enzyme replacement therapy (ERT) in four treated cases (two infantile and two juvenile-adult onsets).The autophagic flux was monitored by measuring the amount of p62-positive protein aggregates and compared, together with fibre vacuolisation, to fibre atrophy.A blocked autophagic flux resulted in p62 accumulation, increased vacuolisation, and progressive atrophy of muscle fibres in biopsies collected from patients during natural history. On the contrary, in the GSDII cases early treated with ERT, the autophagic flux improved and muscle fibre atrophy, fibre vacuolisation, and acid phosphatase activity decreased.The functionality of the autophagy-lysosome system is essential in GSDII muscle, which is characterised by the presence of swollen glycogen-filled lysosomes and autophagic build-up. Defining the role of autophagy and its relationship with muscle loss is critical for understanding the disease pathogenesis, for developing new therapies, and for improving ERT efficacy in GSDII.

Gender difference in limb-girdle muscular dystrophy: a muscle fiber morphometric study in 101 patients.

AIMS: Limb girdle muscular dystrophies (LGMD), a genetically and clinically heterogeneous group of neuromuscular disorders, may show gender differences in the disease severity. We aimed to measure the extent of muscle fiber atrophy and evaluate possible gender differences at fiber level. METHODS: We conducted a thorough morphometric analysis of muscle fiber size and fiber area in 101 muscles from patients with various forms of LGMD (43 LGMD2A, 30 LGMD2B, 21 LGMD2C-2D-2E, 7 LGMD1C) and 12 normal controls. RESULTS: Reduced fiber size (atrophy) was pronounced in LGMD2A and LGMD2B, while LGMD1C showed a significant fiber hypertrophy. When we compared LGMD patients and controls of the same gender, males with LGMD2A and LGMD2B showed significantly higher fiber atrophy than control males, whereas female LGMD patients had similar values to female controls, suggesting a gender difference in muscle fiber atrophy. DISCUSSION: Less recovery to disuse atrophy in men than in women has been attributed to the possibility that in women a smaller initial muscle size associated to endocrine factors could attenuate gender-specific muscle loss. The possibility that males with LGMD may be clinically more severely affected than females has been explored, but the mechanism remains elusive.

Muscle atrophy, ubiquitin-proteasome, and autophagic pathways in dysferlinopathy.

INTRODUCTION: Muscle fiber atrophy and the molecular pathways underlying this process have not been investigated in dysferlinopathy patients. METHODS: In 22 muscles from dysferlinopathy patients we investigated fiber atrophy by morphometry and ubiquitin-proteasome and autophagic pathways using protein and/or transcriptional analysis of atrophy- and autophagy-related genes (MuRF1, atrogin1, LC3, p62, Bnip3). RESULTS: Dysferlinopathy showed significant fiber atrophy and higher MuRF-1 protein and mRNA levels, which correlated with fiber size, suggesting activation of the atrophy program by proteasome induction. CONCLUSIONS: Some of the MuRF-1 upregulation and proteasome induction may be attributed to the prominent regeneration found. A potential role of impaired autophagy was suggested by p62-positive protein aggregates in atrophic fibers and significantly higher levels of LC3-II and p62 proteins and overexpression of p62 and Bnip3 mRNA. Damaged muscle fibers and prominent inflammatory changes may also enhance autophagy due to the insufficient level of proteasomal degradation of mutant dysferlin.

Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon disease.

Danon disease, an X-linked dominant disorder, results from mutations in the lysosome-associated membrane protein-2 (LAMP2) gene and presents with hypertrophic cardiomyopathy, skeletal myopathy, and mental retardation. To investigate the effects of LAMP2 gene mutations on protein expression in different tissues, we screened LAMP2 gene mutations and LAMP-2 protein deficiency in the skeletal muscle of nine unrelated patients with hypertrophic cardiomyopathy and vacuolar myopathy. We identified three novel families (including one affected mother) with unreported LAMP2 gene null mutations and LAMP-2 protein deficiency in skeletal and myocardial muscle, leukocytes, and fibroblasts. LAMP-2 protein deficiency was detectable in various tissues, including leukocytes, explaining the multisystem clinical involvement. Skeletal muscle immunopathology showed that mutant protein was not localized in the Golgi complex, vacuolar membranes expressed sarcolemmal-specific proteins, and the degree of muscle fiber vacuolization correlated with clinical muscle involvement. In our female patient, muscle histopathology and LAMP-2 protein analysis was inconclusive, indicating that diagnosis in females requires mutation identification. The random X-chromosome inactivation found in muscle and leukocytes excluded the possibility that selective involvement of some tissues in females is due to skewed X-chromosome inactivation. Therefore, biochemical analysis of leukocytes might be used for screening in male patients, but genetic screening is required in females.