Haorei Yarreiphang

Bio: Haorei Yarreiphang is an academic researcher from National Institute of Mental Health and Neurosciences. The author has contributed to research in topics: MPTP & Substantia nigra. The author has an hindex of 5, co-authored 7 publications receiving 103 citations.

A novel autophagy modulator 6-Bio ameliorates SNCA/α-synuclein toxicity.

Abstract: Parkinson disease (PD) is a life-threatening neurodegenerative movement disorder with unmet therapeutic intervention. We have identified a small molecule autophagy modulator, 6-Bio that shows clearance of toxic SNCA/α-synuclein (a protein implicated in synucleopathies) aggregates in yeast and mammalian cell lines. 6-Bio induces autophagy and dramatically enhances autolysosome formation resulting in SNCA degradation. Importantly, neuroprotective function of 6-Bio as envisaged by immunohistology and behavior analyses in a preclinical model of PD where it induces autophagy in dopaminergic (DAergic) neurons of mice midbrain to clear toxic protein aggregates suggesting that it could be a potential therapeutic candidate for protein conformational disorders.

Admixing of MPTP-Resistant and Susceptible Mice Strains Augments Nigrostriatal Neuronal Correlates to Resist MPTP-Induced Neurodegeneration

Abstract: Disease genetics in admixed populations like Hispanic-Americans, African-Americans, etc. are gaining importance due to high disease burden in them. Furthermore, epidemiological studies conclusively prove ethnicity-based differential prevalence of Parkinson's disease (PD), since the American-Caucasians are more susceptible than Asian-Indians and Africans. Contradictorily, Anglo-Indians, an admixture of Europeans and Asian-Indians are five-times less susceptible than Indians. We evaluated the neural basis of this phenomenon using the cytomorphological features of susceptibility to nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The nigral dopaminergic neuronal numbers, their size and tyrosine hydroxylase (TH), PitX3 and Nurr1 expression were compared in MPTP-susceptible C57BL/6J mice, MPTP-resistant CD-1 mice and their crossbreds using stereology, morphometry and densitometry. Apoptotic index was evaluated by TUNEL-assay and caspase-3 expression. Striatal volume, TH and glial derived neurotrophic factor (GDNF) expression were studied. The normal CD-1 and crossbreds had significantly more, although smaller, nigral dopaminergic neurons than C57BL/6J, and a larger striatum. The crossbreds had higher TH, Nurr1 and PitX3 levels. MPTP administration caused loss of ~50-60 % nigral dopaminergic neurons in C57BL/6J and ~15 % in CD-1, but none in crossbreds. MPTP-induced cellular shrinkage in C57BL/6J was contrasted by nuclear enlargement without somal alterations in resistant strains. MPTP lowered the striatal TH and GDNF in C57BL/6J. Elevated striatal GDNF in CD-1 and crossbreds could be of compensatory nature and complemented the reduced nigral caspase-3 expression to attenuate and/or block apoptosis. Similar neural correlates of resilience are envisaged in the Anglo-Indian population. Thus, we present the core neuroanatomical features of resilience against PD and evidence for ethnicity-based differential prevalence.

Modulation of Autophagy by a Small Molecule Inverse Agonist of ERRα Is Neuroprotective.

Abstract: Mechanistic insights into aggrephagy, a selective basal autophagy process to clear misfolded protein aggregates, are lacking. Here, we report and describe the role of Estrogen Related Receptor α (ERRα, HUGO Gene Nomenclature ESRRA), new molecular player of aggrephagy, in keeping autophagy flux in check by inhibiting autophagosome formation. A screen for small molecule modulators for aggrephagy identified ERRα inverse agonist XCT 790, that cleared α-synuclein aggregates in an autophagy dependent, but mammalian target of rapamycin (MTOR) independent manner. XCT 790 modulates autophagosome formation in an ERRα dependent manner as validated by siRNA mediated knockdown and over expression approaches. We show that, in a basal state, ERRα is localized on to the autophagosomes and upon autophagy induction by XCT 790, this localization is lost and is accompanied with an increase in autophagosome biogenesis. In a preclinical mouse model of Parkinson's disease (PD), XCT 790 exerted neuroprotective effects in the dopaminergic neurons of nigra by inducing autophagy to clear toxic protein aggregates and, in addition, ameliorated motor co-ordination deficits. Using a chemical biology approach, we unrevealed the role of ERRα in regulating autophagy and can be therapeutic target for neurodegeneration.

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Role of Autophagy in Parkinson's Disease.

Abstract: Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include macroautophagy, chaperone-mediated autophagy and microautophagy, each involving different mechanisms of substrate delivery to lysosome. Defects of these pathways and the resulting accumulation of protein aggregates represent a common pathobiological feature of neurodegenerative disorders such as Alzheimer, Parkinson and Huntington disease. This review provides an overview of the role of autophagy in Parkinson's disease (PD) by summarizing the most relevant genetic and experimental evidence showing how this process can contribute to disease pathogenesis. Given lysosomes take part in the final step of the autophagic process, the role of lysosomal defects in the impairment of autophagy and their impact on disease will also be discussed. A glance on the role of non-neuronal autophagy in the pathogenesis of PD will be included. Moreover, we will examine novel pharmacological targets and therapeutic strategies that, by boosting autophagy, may be theoretically beneficial for PD. Special attention will be focused on natural products, such as phenolic compounds, that are receiving increasing consideration due to their potential efficacy associated with low toxicity. Although many efforts have been made to elucidate autophagic process, the development of new therapeutic interventions requires a deeper understanding of the mechanisms that may lead to autophagy defects in PD and should take into account the multifactorial nature of the disease as well as the phenotypic heterogeneity of PD patients.

Autophagic and endo-lysosomal dysfunction in neurodegenerative disease

Abstract: Due to their post-mitotic state, metabolic demands and often large polarised morphology, the function and survival of neurons is dependent on an efficient cellular waste clearance system both for generation of materials for metabolic processes and removal of toxic components. It is not surprising therefore that deficits in protein clearance can tip the balance between neuronal health and death. Here we discuss how autophagy and lysosome-mediated degradation pathways are disrupted in several neurological disorders. Both genetic and cell biological evidence show the diversity and complexity of vesicular clearance dysregulation in cells, and together may ultimately suggest a unified mechanism for neuronal demise in degenerative conditions. Causative and risk-associated mutations in Alzheimer’s disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson’s disease, Huntington’s disease and others have given the field a unique mechanistic insight into protein clearance processes in neurons. Through their broad implication in neurodegenerative diseases, molecules involved in these genetic pathways, in particular those involved in autophagy, are emerging as appealing therapeutic targets for intervention in neurodegeneration.

Dysfunction of Cellular Proteostasis in Parkinson's Disease.

Abstract: Despite decades of research, current therapeutic interventions for Parkinson's disease (PD) are insufficient as they fail to modify disease progression by ameliorating the underlying pathology. Cellular proteostasis (protein homeostasis) is an essential factor in maintaining a persistent environment for neuronal activity. Proteostasis is ensured by mechanisms including regulation of protein translation, chaperone-assisted protein folding and protein degradation pathways. It is generally accepted that deficits in proteostasis are linked to various neurodegenerative diseases including PD. While the proteasome fails to degrade large protein aggregates, particularly alpha-synuclein (α-SYN) in PD, drug-induced activation of autophagy can efficiently remove aggregates and prevent degeneration of dopaminergic (DA) neurons. Therefore, maintenance of these mechanisms is essential to preserve all cellular functions relying on a correctly folded proteome. The correlations between endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) that aims to restore proteostasis within the secretory pathway are well-established. However, while mild insults increase the activity of chaperones, prolonged cell stress, or insufficient adaptive response causes cell death. Modulating the activity of molecular chaperones, such as protein disulfide isomerase which assists refolding and contributes to the removal of unfolded proteins, and their associated pathways may offer a new approach for disease-modifying treatment. Here, we summarize some of the key concepts and emerging ideas on the relation of protein aggregation and imbalanced proteostasis with an emphasis on PD as our area of main expertise. Furthermore, we discuss recent insights into the strategies for reducing the toxic effects of protein unfolding in PD by targeting the ER UPR pathway.