Mutations in LRRK2 and GBA1 are common genetic risk factors for Parkinson's disease (PD) and major efforts are underway to develop new therapeutics that target LRRK2 or glucocerebrosidase (GCase). ...Here we describe a mechanistic and therapeutic convergence of LRRK2 and GCase in neurons derived from patients with PD. We find that GCase activity was reduced in dopaminergic (DA) neurons derived from PD patients with LRRK2 mutations. Inhibition of LRRK2 kinase activity results in increased GCase activity in DA neurons with either LRRK2 or GBA1 mutations. This increase is sufficient to partially rescue accumulation of oxidized dopamine and alpha-synuclein in PD patient neurons. We have identified the LRRK2 substrate Rab10 as a key mediator of LRRK2 regulation of GCase activity. Together, these results suggest an important role of mutant LRRK2 as a negative regulator of lysosomal GCase activity.
Abstract
Frontotemporal dementia (FTD) is a common neurogenerative disorder characterized by progressive degeneration in the frontal and temporal lobes. Heterozygous mutations in the gene encoding ...progranulin (PGRN) are a common genetic cause of FTD. Recently, PGRN has emerged as an important regulator of lysosomal function. Here, we examine the impact of PGRN mutations on the processing of full-length prosaposin to individual saposins, which are critical regulators of lysosomal sphingolipid metabolism. Using FTD-PGRN patient-derived cortical neurons differentiated from induced pluripotent stem cells, as well as post-mortem tissue from patients with FTLD-PGRN, we show that PGRN haploinsufficiency results in impaired processing of prosaposin to saposin C, a critical activator of the lysosomal enzyme glucocerebrosidase (GCase). Additionally, we found that PGRN mutant neurons had reduced lysosomal GCase activity, lipid accumulation and increased insoluble α-synuclein relative to isogenic controls. Importantly, reduced GCase activity in PGRN mutant neurons is rescued by treatment with saposin C. Together, these findings suggest that reduced GCase activity due to impaired processing of prosaposin may contribute to pathogenesis of FTD resulting from PGRN mutations.
Elementary school students are often placed into groups with peers of similar reading ability for leveled guided reading instruction. Through this practice, students are differentially exposed to ...reading skills, strategies, and texts that are presumed to match their reading ability. This widespread practice is problematic given that (1) current notions of matching early readers to texts for reading instruction are based on traditional instructional practice rather than reading science, (2) poor and minority students are overrepresented in the lowest ranked groups, (3) students in higher ranked groups make greater academic gains than those in lower ranked groups, and (4) teacher perceptions of students' abilities are often inaccurate. Conversely, as supported by research, when students are presented with texts of increased difficulty and given appropriate instructional support, they are able to make accelerated reading progress. The purpose of this design-based research study was to develop innovative classroom practices and theoretical insights regarding the use of non-leveled guided reading instruction in order to support the reading achievement of all students. Qualitative data, in the form of fieldnotes, semi-structured interviews, and documents were collected. Data analysis included structural and process coding which resulted in the explication of five design principles to assist in the application of this design in other contexts. Specific attention is given to the technical, normative, and political aspects inherent in the dissemination and sustainability of the proposed design.
CAF-1 is an evolutionarily conserved H3/H4 histone chaperone that plays a key role in replication-coupled chromatin assembly and is targeted to the replication fork via interactions with PCNA, which, ...if disrupted, leads to epigenetic defects. In
, when the silent mating-type locus
contains point mutations within the
silencer, Sir protein association and silencing is lost. However, mutation of
, encoding an S-phase-specific kinase, or subunits of the H4 K16-specific acetyltransferase complex SAS-I, restore silencing to this crippled
,
Here, we observed that loss of Cac1p, the largest subunit of CAF-1, also restores silencing at
, and silencing in both
Δ and
mutants is suppressed by overexpression of
We demonstrate Cdc7p and Cac1p interact
in S phase, but not in G1, consistent with observed cell cycle-dependent phosphorylation of Cac1p, and hypoacetylation of chromatin at H4 K16 in both
and
Δ mutants. Moreover, silencing at
** is restored in cells expressing cac1p mutants lacking Cdc7p phosphorylation sites. We also discovered that
Δ and
synthetically interact negatively in the presence of DNA damage, but that Cdc7p phosphorylation sites on Cac1p are not required for responses to DNA damage. Combined, our results support a model in which Cdc7p regulates replication-coupled histone modification via a
-dependent mechanism involving H4 K16ac deposition, and thereby silencing, while CAF-1-dependent replication- and repair-coupled chromatin assembly
are functional in the absence of phosphorylation of Cdc7p consensus sites on CAF-1.
Replication-coupled chromatin assembly is achieved by a network of alternate pathways containing different chromatin assembly factors and histone-modifying enzymes that coordinate deposition of ...nucleosomes at the replication fork. Here we describe the organization of a CAF-1-dependent pathway in Saccharomyces cerevisiae that regulates acetylation of histone H4 K16. We demonstrate factors that function in this CAF-1-dependent pathway are important for preventing establishment of silenced states at inappropriate genomic sites using a crippled HMR locus as a model, while factors specific to other assembly pathways do not. This CAF-1-dependent pathway required the cullin Rtt101p, but was functionally distinct from an alternate pathway involving Rtt101p-dependent ubiquitination of histone H3 and the chromatin assembly factor Rtt106p. A major implication from this work is that cells have the inherent ability to create different chromatin modification patterns during DNA replication via differential processing and deposition of histones by distinct chromatin assembly pathways within the network.
Aging in Community Black, Kathy; Dobbs, Debra; Young, Tiffany L.
Journal of applied gerontology,
03/2015, Volume:
34, Issue:
2
Journal Article
Peer reviewed
Dignity and independence are widely considered as core concepts to aging well, yet little research has explored how older adults perceive these issues in the context of community life. Moreover, ...little is known regarding the ways in which the broader public views and enhances aging with dignity and independence with their older residents. Using participatory action research, multiple methods of qualitative inquiry, and tenets of appreciative inquiry, this article reports on a community-based initiative aimed to better understand the positive aspects of aging with dignity and independence. Synthesized findings yielded 6 “actionable themes”: (1) meaningful involvement, (2) aging in place, (3) respect and inclusion, (4) communication and information, (5) transportation and mobility, and (6) health and well-being. The findings invoke a new paradigm for community aging that highlights the unique contributions of older adults as a core social resource. Implications for mobilizing community action to promote aging with dignity and independence are discussed.
Introduction/Purpose Efforts to improve chronic disease outcomes among US adults highlight families, particularly support from families, as a key aspect of disease prevention and management. To date, ...however, an overwhelming focus on individual-level outcomes and unidirectional support (eg, from a family caregiver to an identified care recipient) belies the existence of co-occurring health concerns and interdependent care. There are increasing calls for more sophisticated and intensive family health interventions that better integrate family-level factors, processes, and outcomes to provide comprehensive family support services in health care and community-based settings. Methods This commentary provides key considerations for advancing this work while centering family health equity and families themselves in health initiatives. Results Several critical barriers are identified and discussed. For example, a narrow focus on family and inadequate measures of family-level disease burden make it challenging to understand how the disproportionate burden of chronic disease observed among individuals of lower socioeconomic status and certain racial and ethnic groups compounds and complicates family health experiences. In addition, limited attention to the interaction between individuals, families, and broader sociocultural factors that influence family resources and constraints, such as racism, hamper program design, implementation, and evaluation. Conclusion To center families in efforts to reduce chronic disease disparities, it is necessary to move beyond superficial attention to the complexity of disease prevention and management within the family context. This commentary serves to enhance understanding of important drivers of family-level chronic disease outcomes, while providing important considerations for advancing research and practice.
Chronic diseases are common among African Americans, but the extent to which research has focused on addressing chronic diseases across multiple members of African American families is unclear. This ...systematic scoping review summarizes the characteristics of research addressing coexisting chronic conditions among African American families, including guiding theories, conditions studied, types of relationships, study outcomes, and intervention research.
The literature search was conducted in PsycInfo, PubMed, Social Work Abstracts, Sociological Abstracts, CINAHL, and Family and Society Studies Worldwide to identify relevant articles published from January 2000 through September 2016. We screened the title and abstracts of 9,170 articles, followed by full-text screening of 530 articles, resulting in a final sample of 114 articles. Fifty-seven percent (n = 65) of the articles cited a guiding theory/framework, with psychological theories (eg, social cognitive theory, transtheoretical model) being most prominent. The most common conditions studied in families were depression (70.2%), anxiety (23.7%), and diabetes (22.8%), with most articles focusing on a combination of physical and mental health conditions (47.4%).
In the 114 studies in this review, adult family members were primarily the index person (71.1%, n = 81). The index condition, when identified (79.8%, n = 91), was more likely to be a physical health condition (46.5%, n = 53) than a mental health condition (29.8%, n = 34). Among 343 family relationships examined, immediate family relationships were overwhelmingly represented (85.4%, n = 293); however, extended family (12.0%, n = 41) and fictive kin (0.6%, n = 2) were included. Most (57.0%, n = 65) studies focused on a single category of outcomes, such as physical health (eg, obesity, glycemic control), mental health (eg, depression, anxiety, distress), psychosocial outcomes (eg, social support, caregiver burden), or health behaviors (eg, medication adherence, disease management, health care utilization); however, 43.0% (n = 49) of studies focused on outcomes across multiple categories. Sixteen intervention articles (14.0%) were identified, with depression the most common condition of interest.
Recognizing the multiple, simultaneous health issues facing families through a lens of family comorbidity and family multimorbidity may more accurately mirror the lived experiences of many African American families and better elucidate intervention opportunities than previous approaches.
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