Life-Course Mobility in Socioeconomic Position and High Depressive Symptoms Among Young Black Women: The SELF Study.

BACKGROUND: Current literature on the association between mobility in socioeconomic position (SEP) and depression demonstrates mixed findings, with variation in the benefits of upward SEP by racial group and ethnic background. No study has examined life-course SEP mobility and depressive symptoms among Black women in the United States. METHODS: Our cohort included 1,612 Black women enrolled in the Study of Environment, Lifestyle and Fibroids between 2010 and 2012 and followed for 5 years. We used data on socioeconomic indicators at childhood and adulthood and used latent class analysis to create a life-course SEP mobility measure (persistently low, downward, upward, and persistently high). Using the 11-item Center for Epidemiologic Studies Depression Scale (CES-D), we assessed high (≥9) versus low depressive symptoms. Multivariable log risk models were used to produce risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Of the participants, 37% had high depressive symptoms. Persistently low (RR, 1.56; 95% CI, 1.31-1.86) and downward (RR, 1.36; 95% CI, 1.14-1.63) SEP mobility was associated with high depressive symptoms after adjustment for age, adult social support, and marital status. There was evidence of an effect measure modification by adult social support, with a stronger association among those who reported high adult social support compared with low adult social support. CONCLUSIONS: These findings suggest directing mental health resources to people experiencing low SEP at any stage in life, especially those with low SEP in adulthood, to aid in the management of depressive symptoms.

Neighborhood disadvantage and immune-related illnesses among residents living in the US Gulf States.

PURPOSE: Neighborhood disadvantage has been associated with increased risk for pneumonia and influenza-associated hospitalizations. Few studies, however, have investigated how neighborhood disadvantage may influence immune-related illnesses. The aim of this study was to examine the association between neighborhooddisadvantage and immune-related illnesses. METHODS: We used data from the Gulf Long-term Follow-up (GuLF) Study (n = 32,608). Our analytic sample included home visit participants (n = 11,193) who had complete information on exposure and covariates (n = 10,543). Neighborhood disadvantage was assessed using the 2013 Area Deprivation Index (ADI), which assigns a ranking of 1 to 100 for lowest to highest disadvantage. We linked ADI to participants' geocoded enrollment addresses at the census block group level. ADI was categorized into quartiles based on the national distribution with the first quartile as the referent. Immune-related illnesses self-reported at the home visit (May 2011-May 2013) included occurrence of shingles, pneumonia, cold sores, flu, and colds since the Deepwater Horizon oil spill (April 2010). Frequent colds and frequent flu were defined as ≥4 colds and ≥2 episodes of flu since the spill. An aggregated outcome, based on occurrence of any pneumonia, cold sores, flu, and ≥4 colds since the spill, was also examined. We assessed the association of each outcome with ADI using multivariable log-binomial regression adjusting for individual-level demographics, behavioral factors, kids at home, and season of interview completion. RESULTS: We found elevated prevalence ratios (PR) and 95% confidence intervals (CI) for pneumonia associated with ADI in the third (PR: 2.04, 95% CI: 1.04, 4.02) and fourth (PR: 2.00; 95% CI: 1.00, 3.98) quartiles. PRs for frequent colds were also elevated for increasing ADI quartiles, but with confidence intervals including the null value. CONCLUSIONS: The observed associations of frequent colds and pneumonia with increasing neighborhood disadvantage may warrant further research on this topic.

Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 (SCA1) is an incurable, dominantly inherited neurodegenerative disease of the cerebellum caused by a polyglutamine-repeat expansion in the protein ataxin-1 (ATXN1). While analysis of human autopsy material indicates significant glial pathology in SCA1, previous research has focused on characterizing neuronal dysfunction. In this study, we characterized astrocytic and microglial response in SCA1 using a comprehensive array of mouse models. We have discovered that astrocytes and microglia are activated very early in SCA1 pathogenesis even when mutant ATXN1 expression was limited to Purkinje neurons. Glial activation occurred in the absence of neuronal death, suggesting that glial activation results from signals emanating from dysfunctional neurons. Finally, in all different models examined glial activation closely correlated with disease progression, supporting the development of glial-based biomarkers to follow disease progression.

In cis autosomal dominant mutation of Senataxin associated with tremor/ataxia syndrome.

Senataxin mutations are the molecular basis of two distinct syndromes: (1) ataxia oculomotor apraxia type 2 (AOA2) and (2) juvenile amyotrophic lateral sclerosis 4 (ALS4). The authors describe clinical and molecular genetic studies of mother and daughter who display symptoms of cerebellar ataxia/atrophy, oculomotor defects, and tremor. Both patients share Senataxin mutations N603D and Q653K in cis (N603D-Q653K), adjacent to an N-terminal domain thought to function in protein-protein interaction. The N-terminal and helicase domains appear to harbor missense mutation clusters associated with AOA2 and ALS4. Working synergistically, the N603D-Q653K mutations may confer a partial dominant negative effect, acting on the senataxin N-terminal, further expanding the phenotypic spectrum associated with Senataxin mutations.

Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice.

Many neurodegenerative diseases are caused by gain-of-function mechanisms in which the disease-causing protein is altered, becomes toxic to the cell, and aggregates. Among these 'proteinopathies' are Alzheimer's and Parkinson's disease, prion disorders and polyglutamine diseases. Members of this latter group, also known as triplet repeat diseases, are caused by the expansion of unstable CAG repeats coding for glutamine within the respective proteins. Spinocerebellar ataxia type 1 (SCA1) is one such disease, characterized by loss of motor coordination due to the degeneration of cerebellar Purkinje cells and brain stem neurons. In SCA1 and several other polyglutamine diseases, the expanded protein aggregates into nuclear inclusions (NIs). Because these NIs accumulate molecular chaperones, ubiquitin and proteasomal subunits--all components of the cellular protein re-folding and degradation machinery--we hypothesized that protein misfolding and impaired protein clearance might underlie the pathogenesis of polyglutamine diseases. Over-expressing specific chaperones reduces protein aggregation in transfected cells and suppresses neurodegeneration in invertebrate animal models of polyglutamine disorders. To determine whether enhancing chaperone activity could mitigate the phenotype in a mammalian model, we crossbred SCA1 mice with mice over-expressing a molecular chaperone (inducible HSP70 or iHSP70). We found that high levels of HSP70 did indeed afford protection against neurodegeneration.

Alterations in neural intermediate filament organization: functional implications and the induction of pathological changes related to motor neuron disease.

The properties regulating the supramolecular organization of neural intermediate filament (NIF) networks have been investigated in cultured dorsal root ganglion (DRG) neurons. The studies described take advantage of the ability of endogenous NIF to incorporate purified biotinylated neurofilament triplet (NFT) proteins, NF-L, NF-M and NF-H. When injected at concentrations of 0.8-1.0 mg/ml injection buffer, each of these proteins is incorporated without perturbing the endogenous NIF network. However, at progressively higher concentrations, NF-H induces the aggregation and accumulation of NIF in the cell body. Subsequent to the induction of these aggregates, numerous alterations in the cytoarchitecture of neurons can be detected. The latter occur in a temporal sequence which appears to begin with the fragmentation of the Golgi complex. At later times, accumulation of mitochondria within the proximal region of neurites, peripheralization of the nucleus, and a significant decrease in neurite caliber become obvious. After longer time periods, the NIF aggregates are seen to react with an antibody which reveals abnormally phosphorylated NF-H. These observations demonstrate that an imbalance in the normal stoichiometric relationships among the NFT proteins rapidly alters the supramolecular organization of the NIF network. These changes most likely reflect the normal functions of neurofilaments in cell shape and the organization and cytoplasmic distribution of membranous organelles. Interestingly, virtually all of these changes closely resemble those which have been reported in motor neuron diseases such as amyotrophic lateral sclerosis (ALS). These findings suggest that cultured neurons can be used as models for more precisely defining the relationships between the formation of NIF aggregates and the sequence of cytopathological events which typify neurodegenerative diseases.

The function of intermediate filaments in cell shape and cytoskeletal integrity.

This study describes the development and use of a specific method for disassembling intermediate filament (IF) networks in living cells. It takes advantage of the disruptive effects of mimetic peptides derived from the amino acid sequence of the helix initiation 1A domain of IF protein chains. The results demonstrate that at 1:1 molar ratios, these peptides disassemble vimentin IF into small oligomeric complexes and monomers within 30 min at room temperature in vitro. Upon microinjection into cultured fibroblasts, these same peptides induce the rapid disassembly of IF networks. The disassembly process is accompanied by a dramatic alteration in cell shape and the destabilization of microtubule and actin-stress fiber networks. These changes in cell shape and IF assembly states are reversible. The results are discussed with respect to the roles of IF in cell shape and the maintenance of the integrity and mechanical properties of the cytoplasm, as well as the stability of the other major cytoskeletal systems.

The relative roles of specific N- and C-terminal phosphorylation sites in the disassembly of intermediate filament in mitotic BHK-21 cells.

Previously we identified p34cdc2 as one of two protein kinases mediating the hyperphosphorylation and disassembly of vimentin in mitotic BHK-21 cells. In this paper, we identify the second kinase as a 37 kDa protein. This p37 protein kinase phosphorylates vimentin on two adjacent residues (thr-457 and ser-458) which are located in the C-terminal non-alpha-helical domain. Contrary to the p34cdc2 mediated N-terminal phosphorylation (at ser-55) which can disassemble vimentin intermediate filaments (IF) in vitro, p37 protein kinase phosphorylates vimentin-IF without obviously affecting its structure in vitro. We have further examined the in vivo role(s) of vimentin phosphorylation in the disassembly of the IF network in mitotic BHK cells by transient transfection assays. In untransfected BHK cells, the interphase vimentin IF networks are disassembled into non-filamentous aggregates when cells enter mitosis. Transfection of cells with vimentin cDNA lacking the p34cdc2 phosphorylation site (ser55:ala) effectively prevents mitotic cells from disassembling their IF. In contrast, apparently normal disassembly takes place in cells transfected with cDNA containing mutated p37 kinase phosphorylation sites (thr457:ala/ser458:ala). Transfection of cells with vimentin cDNAs lacking both the N- and C-terminal phosphorylation sites yields a phenotype indistinguishable from that obtained with the single N-terminal mutant. Taken together, our results demonstrate that the site-specific phosphorylation of the N-terminal domain, but not the C-terminal domain of vimentin plays an important role in determining the state of IF polymerization and supramolecular organization in mitotic cells.

Intermediate filament dynamics.

The view of intermediate filaments as static cytoskeletal elements is changing. Studies of exogenous intermediate filament proteins, either microinjected or expressed from transfected genes, have demonstrated that a continuous incorporation of subunits into the polymerized filaments is taking place. This incorporation appears to be required for maintaining normal cytoplasmic networks of intermediate filaments. At the post-translational level, phosphorylation is an important factor in regulating dynamic aspects of intermediate filament organization and structure.