MyMedR

Displaying all 9 publications

Abstract:

Sort:

Antioxidant modulation in restoring mitochondrial function in neurodegeneration

Pahrudin Arrozi A, Wan Ngah WZ, Mohd Yusof YA, Ahmad Damanhuri MH, Makpol S

Int J Neurosci, 2017 Mar;127(3):218-235.
PMID: 27074540 DOI: 10.1080/00207454.2016.1178261

Alzheimer's disease (AD) and Parkinson's disease (PD) are the leading causes of disability associated with neurodegeneration worldwide. These diseases are influenced by multiple genetic and environmental factors and share similar mechanisms as both are characterized by accumulation and aggregation of misfolded proteins - amyloid-beta (Aβ) in AD and α-synuclein in PD. Over the past decade, increasing evidence has shown that mitochondrial dysfunction and the generation of reactive oxygen species (ROS) are involved in the pathology of these diseases, and the contributions of these defects to the cellular and molecular changes that eventually cause neuronal death have been explored. Using mitochondrial protective agents, such as antioxidants, to combat ROS provides a new strategy for neurodegenerative treatment. In this review, we highlight the potential of multiple types of antioxidants, including vitamins, phytochemicals, fatty acids and minerals, as well as synthetic antioxidants specifically targeting the mitochondria, which can restore mitochondrial function, in the treatment of neurodegenerative disorders at both the pre-clinical and clinical stages by focusing on AD and PD.

Matched MeSH terms: Neurodegenerative Diseases/pathology
Emerging role of S100B protein implication in Parkinson's disease pathogenesis

Angelopoulou E, Paudel YN, Piperi C

Cell Mol Life Sci, 2021 Feb;78(4):1445-1453.
PMID: 33052436 DOI: 10.1007/s00018-020-03673-x

The exact etiology of Parkinson's disease (PD) remains obscure, lacking effective diagnostic and prognostic biomarkers. In search of novel molecular factors that may contribute to PD pathogenesis, emerging evidence highlights the multifunctional role of the calcium-binding protein S100B that is widely expressed in the brain and predominantly in astrocytes. Preclinical evidence points towards the possible time-specific contributing role of S100B in the pathogenesis of neurodegenerative disorders including PD, mainly by regulating neuroinflammation and dopamine metabolism. Although existing clinical evidence presents some contradictions, estimation of S100B in the serum and cerebrospinal fluid seems to hold a great promise as a potential PD biomarker, particularly regarding the severity of motor and non-motor PD symptoms. Furthermore, given the recent development of S100B inhibitors that are able to cross the blood brain barrier, novel opportunities are arising in the research field of PD therapeutics. In this review, we provide an update on recent advances in the implication of S100B protein in the pathogenesis of PD and discuss relevant studies investigating the biomarker potential of S100B in PD, aiming to shed more light on clinical targeting approaches related to this incurable disorder.

Matched MeSH terms: Neurodegenerative Diseases/pathology
Antioxidant Modulation of mTOR and Sirtuin Pathways in Age-Related Neurodegenerative Diseases

Abdullah A, Mohd Murshid N, Makpol S

Mol Neurobiol, 2020 Dec;57(12):5193-5207.
PMID: 32865663 DOI: 10.1007/s12035-020-02083-1

In the human body, cell division and metabolism are expected to transpire uneventfully for approximately 25 years. Then, secondary metabolism and cell damage products accumulate, and ageing phenotypes are acquired, causing the progression of disease. Among these age-related diseases, neurodegenerative diseases have attracted considerable attention because of their irreversibility, the absence of effective treatment and their relationship with social and economic pressures. Mechanistic (formerly mammalian) target of rapamycin (mTOR), sirtuin (SIRT) and insulin/insulin growth factor 1 (IGF1) signalling pathways are among the most important pathways in ageing-associated conditions, such as neurodegeneration. These longevity-related pathways are associated with a diversity of various processes, including metabolism, cognition, stress reaction and brain plasticity. In this review, we discuss the roles of sirtuin and mTOR in ageing and neurodegeneration, with an emphasis on their regulation of autophagy, apoptosis and mitochondrial energy metabolism. The intervention of neurodegeneration using potential antioxidants, including vitamins, phytochemicals, resveratrol, herbals, curcumin, coenzyme Q10 and minerals, specifically aimed at retaining mitochondrial function in the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease is highlighted.

Matched MeSH terms: Neurodegenerative Diseases/pathology*
Proteostasis disruption and senescence in Alzheimer's disease pathways to neurodegeneration

Thapa R, Ahmad Bhat A, Shahwan M, Ali H, PadmaPriya G, Bansal P, et al.

Brain Res, 2024 Dec 15;1845:149202.
PMID: 39216694 DOI: 10.1016/j.brainres.2024.149202

Alzheimer's Disease (AD) is a progressive neurological disease associated with behavioral abnormalities, memory loss, and cognitive impairment that cause major causes of dementia in the elderly. The pathogenetic processes cause complex effects on brain function and AD progression. The proper protein homeostasis, or proteostasis, is critical for cell health. AD causes the buildup of misfolded proteins, particularly tau and amyloid-beta, to break down proteostasis, such aggregates are toxic to neurons and play a critical role in AD pathogenesis. The rise of cellular senescence is accompanied by aging, marked by irreversible cell cycle arrest and the release of pro-inflammatory proteins. Senescent cell build-up in the brains of AD patients exacerbates neuroinflammation and neuronal degeneration. These cells senescence-associated secretory phenotype (SASP) also disturbs the brain environment. When proteostasis failure and cellular senescence coalesce, a cycle is generated that compounds each other. While senescent cells contribute to proteostasis breakdown through inflammatory and degradative processes, misfolded proteins induce cellular stress and senescence. The principal aspects of the neurodegenerative processes in AD are the interaction of cellular senescence and proteostasis failure. This review explores the interconnected roles of proteostasis disruption and cellular senescence in the pathways leading to neurodegeneration in AD.

Matched MeSH terms: Neurodegenerative Diseases/pathology
Fulltext Emerging pathways to neurodegeneration: Dissecting the critical molecular mechanisms in Alzheimer's disease, Parkinson's disease

Tan SH, Karri V, Tay NWR, Chang KH, Ah HY, Ng PQ, et al.

Biomed Pharmacother, 2019 Mar;111:765-777.
PMID: 30612001 DOI: 10.1016/j.biopha.2018.12.101

Neurodegenerative diseases are usually sporadic in nature and commonly influenced by a wide range of genetic, life style and environmental factors. A unifying feature of Alzheimer's disease (AD) and Parkinson's disease (PD) is the abnormal accumulation and processing of mutant or damaged intra and extracellular proteins; this leads to neuronal vulnerability and dysfunction in the brain. Through a detailed review of ubiquitin proteasome, mRNA splicing, mitochondrial dysfunction, and oxidative stress pathway interrelation on neurodegeneration can improve the understanding of the disease mechanism. The identified pathways common to AD and PD nominate promising new targets for further studies, and as well as biomarkers. These insights suggested would likely provide major stimuli for developing unified treatment approaches to combat neurodegeneration. More broadly, pathways can serve as vehicles for integrating findings from diverse studies of neurodegeneration. The evidence examined in this review provides a brief overview of the current literature on significant pathways in promoting in AD, PD. Additionally, these insights suggest that biomarkers and treatment strategies may require simultaneous targeting of multiple components.

Matched MeSH terms: Neurodegenerative Diseases/pathology
Fulltext Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease

Vergnano M, Mockenhaupt M, Benzian-Olsson N, Paulmann M, Grys K, Mahil SK, et al.

Am J Hum Genet, 2020 09 03;107(3):539-543.
PMID: 32758448 DOI: 10.1016/j.ajhg.2020.06.020

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

Matched MeSH terms: Neurodegenerative Diseases/pathology
Fulltext Honey, Propolis, and Royal Jelly: A Comprehensive Review of Their Biological Actions and Health Benefits

Pasupuleti VR, Sammugam L, Ramesh N, Gan SH

Oxid Med Cell Longev, 2017;2017:1259510.
PMID: 28814983 DOI: 10.1155/2017/1259510

BACKGROUND: There are several health benefits that honeybee products such as honey, propolis, and royal jelly claim toward various types of diseases in addition to being food.
SCOPE AND APPROACH: In this paper, the effects of honey, propolis, and royal jelly on different metabolic diseases, cancers, and other diseases have been reviewed. The modes of actions of these products have also been illustrated for purposes of better understanding.
KEY FINDINGS AND CONCLUSIONS: An overview of honey, propolis, and royal jelly and their biological potentials was highlighted. The potential health benefits of honey, such as microbial inhibition, wound healing, and its effects on other diseases, are described. Propolis has been reported to have various health benefits related to gastrointestinal disorders, allergies, and gynecological, oral, and dermatological problems. Royal jelly is well known for its protective effects on reproductive health, neurodegenerative disorders, wound healing, and aging. Nevertheless, the exact mechanisms of action of honey, propolis, and royal jelly on the abovementioned diseases and activities have not been not fully elucidated, and further research is warranted to explain their exact contributions.

Matched MeSH terms: Neurodegenerative Diseases/pathology
Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease

Ishiura H, Shibata S, Yoshimura J, Suzuki Y, Qu W, Doi K, et al.

Nat Genet, 2019 08;51(8):1222-1232.
PMID: 31332380 DOI: 10.1038/s41588-019-0458-z

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

Matched MeSH terms: Neurodegenerative Diseases/pathology
Fulltext Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, et al.

Am J Hum Genet, 2016 Oct 06;99(4):950-961.
PMID: 27666374 DOI: 10.1016/j.ajhg.2016.08.005

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

Matched MeSH terms: Neurodegenerative Diseases/pathology