Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid β (Aβ) accumulation, extracellular Aβ deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD. IntroductionFamilial Alzheimer disease (AD) mutations increase the toxicity and amyloidogenicity of the amyloid β (Aβ) peptide, placing disruption of amyloid precursor protein (APP) metabolism and Aβ production at the center of AD pathogenesis (1). However, less than 2% of AD cases are caused by autosomal-dominant mutations. Familial AD caused by these mutations and the remaining nondominant sporadic AD cases are pathologically similar. Therefore, factors that disrupt APP metabolism and Aβ production, such as increased APP transcription, increased production of amyloidogenic Aβ (2), and decreased APP degradation, may contribute to the pathogenesis of sporadic AD as well.The etiology of AD is distinct from that of other neurodegenerative diseases, such as Parkinson disease and Huntington disease (HD), but all are characterized pathologically by the presence of abnormal protein aggregates and neuronal death (3, 4). Protein aggregates may form by abnormal folding or proteolytic processing of proteins or by the disturbance of intracellular protein degradation pathways (3,5). Autophagy is involved in the intracellular degradation of aggregation-prone α-synuclein (6) and huntingtin

SUMMARY HIV-infected individuals are living longer on antiretroviral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV− individuals. First, we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across >80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA). We find that decreased HLA methylation is predictive of lower CD4/CD8 T cell ratio, linking molecular aging, epigenetic regulation and disease progression.

Background The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. Objective To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared to neurologically healthy normal controls (NC) and Alzheimer’s disease (AD) as dementia controls. Design Case control. Setting Academic medical centres. Participants 129 svPPA, 39 PGRN, 186 NC, and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN, and NC cohorts underwent serum analysis for tumor necrosis factor α (TNF-α) levels. Outcome Measures Chi-square comparison of autoimmune prevalence and follow up logistic regression. Results There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders, and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared to NC. Conclusions svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared to NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 (TDP-43) aggregation.

Endoplasmic reticulum (ER)-associated degradation (ERAD) removes misfolded proteins from the ER membrane and lumen by the ubiquitin-proteasome pathway. Retrotranslocation of ubiquitinated substrates to the cytosol is a universal feature of ERAD that requires the Cdc48 AAA-ATPase. Despite intense efforts, the mechanism of ER exit, particularly for integral membrane (ERAD-M) substrates, has remained unclear. Using a self-ubiquitinating substrate (SUS), which undergoes normal retrotranslocation independently of known ERAD factors, and the new SPOCK (single plate orf compendium kit) micro-library to query all yeast genes, we found the rhomboid derlin Dfm1 was required for retrotranslocation of both HRD and DOA ERAD pathway integral membrane substrates. Dfm1 recruited Cdc48 to the ER membrane with its unique SHP motifs, and it catalyzed substrate extraction through its conserved rhomboid motifs. Surprisingly, dfm1Δ can undergo rapid suppression, restoring wild-type ERAD-M. This unexpected suppression explained earlier studies ruling out Dfm1, and it revealed an ancillary ERAD-M retrotranslocation pathway requiring Hrd1.