scispace - formally typeset
Search or ask a question
Author

Zachary J Ziemba

Bio: Zachary J Ziemba is an academic researcher from University of Michigan. The author has contributed to research in topics: Autophagy & Chaperone-mediated autophagy. The author has an hindex of 1, co-authored 1 publications receiving 3 citations.

Papers
More filters
Journal ArticleDOI
TL;DR: This work disentangles previously misunderstood roles of PI3Ks in CMA regulation, and reports that inhibition of class IPI3K activates chaperone-mediated autophagy in cultured cells and mice.
Abstract: Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo.

16 citations


Cited by
More filters
Journal ArticleDOI
31 Jan 2022-Neuron
TL;DR: The term autophagy encompasses different pathways that route cytoplasmic material to lysosomes for degradation and includes macroautophagy, chaperone-mediated autophathy, and microautophathy as discussed by the authors .

86 citations

Journal ArticleDOI
TL;DR: In this paper, the authors summarize evidence for the contribution of autophagy to health and lifespan and provide examples of the bidirectional interplay between autophagic pathways and several of the so-called hallmarks of aging.

59 citations

Journal ArticleDOI
TL;DR: In this paper , the authors provided an overview of the impact of autophagy on Alzheimer's disease pathophysiology, reviewed the therapeutics that upregulate autoophagy and are currently used in the treatment of other diseases, including cancers, and evaluated their repurposing as a possible treatment option for AD.

17 citations

Journal ArticleDOI
01 Aug 2022-Cells
TL;DR: This review summarizes the changes in the PAM signaling pathway in different subtypes of breast cancer, and the latest research progress about the biomarkers and clinical application of PAM-targeted inhibitors.
Abstract: Phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB/AKT) and mechanistic target of rapamycin (mTOR) (PAM) pathways play important roles in breast tumorigenesis and confer worse prognosis in breast cancer patients. The inhibitors targeting three key nodes of these pathways, PI3K, AKT and mTOR, are continuously developed. For breast cancer patients to truly benefit from PAM pathway inhibitors, it is necessary to clarify the frequency and mechanism of abnormal alterations in the PAM pathway in different breast cancer subtypes, and further explore reliable biomarkers to identify the appropriate population for precision therapy. Some PI3K and mTOR inhibitors have been approved by regulatory authorities for the treatment of specific breast cancer patient populations, and many new-generation PI3K/mTOR inhibitors and AKT isoform inhibitors have also been shown to have good prospects for cancer therapy. This review summarizes the changes in the PAM signaling pathway in different subtypes of breast cancer, and the latest research progress about the biomarkers and clinical application of PAM-targeted inhibitors.

12 citations

Journal ArticleDOI
TL;DR: In this article, the authors discuss the role of apoptosis in human health and its malfunction in several diseases and discuss the path to the morphological and molecular discovery of autophagy.
Abstract: Research in biomedical sciences has changed dramatically over the past fifty years. There is no doubt that the discovery of apoptosis and autophagy as two highly synchronized and regulated mechanisms in cellular homeostasis are among the most important discoveries in these decades. Along with the advancement in molecular biology, identifying the genetic players in apoptosis and autophagy has shed light on our understanding of their function in physiological and pathological conditions. In this review, we first describe the history of key discoveries in apoptosis with a molecular insight and continue with apoptosis pathways and their regulation. We touch upon the role of apoptosis in human health and its malfunction in several diseases. We discuss the path to the morphological and molecular discovery of autophagy. Moreover, we dive deep into the precise regulation of autophagy and recent findings from basic research to clinical applications of autophagy modulation in human health and illnesses and the available therapies for many diseases caused by impaired autophagy. We conclude with the exciting crosstalk between apoptosis and autophagy, from the early discoveries to recent findings.

12 citations