Differential expression of calbindin in nigral dopaminergic neurons in two mice strains with differential susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Vidyadhara, D J; Yarreiphang, Haorei; Abhilash, P.L.; Raju, T.R.; Alladi, Phalguni Anand

doi:10.1016/j.jchemneu.2016.01.001

Cited by 17 publications

(13 citation statements)

References 51 publications

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“…These spatial challenges to address a unique structural geometry, high metabolic demand, enhanced responsiveness to chemical/electrical stimulation, and the requirement for longevity because of their postmitotic nature, place a tremendous burden on the E‐L system. Nigrostriatal dopaminergic neurons have an additional burden in terms of long and highly branched axons, larger surface area, selective transporters for external toxins, large fluctuations in free Ca 2+ , less buffering capacity, and higher oxidative stress, reducing their threshold for degeneration (Vidyadhara et al ; Surmeier et al ; Vidyadhara et al ; Vidyadhara et al ). These vulnerabilities are further exacerbated with aging.…”

Section: Endolysosomal System In Neurons: Custom‐made For Neuronal Fumentioning

confidence: 99%

Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

116

105

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting 1–1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E‐L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin‐mediated synaptic endocytosis, an integral part of the neuronal E‐L system, is probably the main early target as evident in auxilin, RME‐8, and synaptojanin‐1 mutations that cause PD. Autophagy, another important pathway in the E‐L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life‐time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi‐compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α‐synuclein and LRRK2, key proteins involved in PD, function in different steps of the E‐L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E‐L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue “Synuclein”.

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Section: Endolysosomal System In Neurons: Custom‐made For Neuronal Fumentioning

confidence: 99%

Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

116

105

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“…Sustained in time and enhanced by aging processes, oxidative stress may eventually lead to the death of nigrostriatal neurons featuring PD. Following this premise, studies have employed primary neuron cultures (Pacelli et al, 2015), rat brain slices (Carbone et al, 2017), rodents (Vidyadhara et al, 2016) and primate (Dopeso-Reyes et al, 2014) models to demonstrate that nigrostriatal dopaminergic neurons are more vulnerable to neurotoxins that induce PD-like phenotypes in comparison to other neuronal populations, exemplarily dopaminergic neurons lodged in the neighboring ventral tegmental area.…”

Section: Parkinson’s Disease and The Vulnerability Of The Nigrostriatmentioning

confidence: 99%

Diabetes, a Contemporary Risk for Parkinson’s Disease: Epidemiological and Cellular Evidences

Sergi

Renaud

Simola

et al. 2019

Front. Aging Neurosci.

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Diabetes mellitus (DM), a group of diseases characterized by defective glucose metabolism, is the most widespread metabolic disorder affecting over 400 million adults worldwide. This pathological condition has been implicated in the pathogenesis of a number of central encephalopathies and peripheral neuropathies. In further support of this notion, recent epidemiological evidence suggests a link between DM and Parkinson’s disease (PD), with hyperglycemia emerging as one of the culprits in neurodegeneration involving the nigrostriatal pathway, the neuroanatomical substrate of the motor symptoms affecting parkinsonian patients. Indeed, dopaminergic neurons located in the mesencephalic substantia nigra appear to be particularly vulnerable to oxidative stress and degeneration, likely because of their intrinsic susceptibility to mitochondrial dysfunction, which may represent a direct consequence of hyperglycemia and hyperglycemia-induced oxidative stress. Other pathological pathways induced by increased intracellular glucose levels, including the polyol and the hexosamine pathway as well as the formation of advanced glycation end-products, may all play a pivotal role in mediating the detrimental effects of hyperglycemia on nigral dopaminergic neurons. In this review article, we will examine the epidemiological as well as the molecular and cellular clues supporting the potential susceptibility of nigrostriatal dopaminergic neurons to hyperglycemia.

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“…Quantification of the absolute number of TH-ir dopaminergic neurons was performed using unbiased stereology [31,32] using a 10X objective of Olympus BX61 Microscope equipped with StereoInvestigator (Software Version 8.1, Micro-brightfield Inc., Colchester, USA). Stereological quatification for dopaminergic neuronal number was performed using optical fractionator probe of the StereoInvestigator [6,7].…”

Section: Number Of Th-ir Dopaminergic Neurons and Iba1-ir Microglia Imentioning

confidence: 99%

Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration

Pandurangi

Murumalla

et al. 2019

EBioMedicine

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BackgroundPlethora of efforts fails to yield a single drug to reverse the pathogenesis of Parkinson's disease (PD) and related α-synucleopathies.MethodsUsing chemical biology, we identified a small molecule inhibitor of c-abl kinase, PD180970 that could potentially clear the toxic protein aggregates. Genetic, molecular, cell biological and immunological assays were performed to understand the mechanism of action. In vivo preclinical disease model of PD was used to assess its neuroprotection efficacy.FindingsIn this report, we show the ability of a small molecule inhibitor of tyrosine kinases, PD180970, to induce autophagy (cell lines and mice midbrain) in an mTOR-independent manner and ameliorate the α-synuclein mediated toxicity. PD180970 also exerts anti-neuroinflammatory potential by inhibiting the release of proinflammatory cytokines such as IL-6 (interleukin-6) and MCP-1 (monocyte chemoattractant protein-1) through reduction of TLR-4 (toll like receptor-4) mediated NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation. In vivo studies show that PD180970 is neuroprotective by degrading the toxic protein oligomers through induction of autophagy and subsiding the microglial activation.InterpretationThese protective mechanisms ensure the negation of Parkinson's disease related motor impairments.FundThis work was supported by Wellcome Trust/DBT India Alliance Intermediate Fellowship (500159-Z-09-Z), DST-SERB grant (EMR/2015/001946), DBT (BT/INF/22/SP27679/2018) and JNCASR intramural funds to RM, and SERB, DST (SR/SO/HS/0121/2012) to PAA, and DST-SERB (SB/YS/LS-215/2013) to JPC and BIRAC funding to ETA C-CAMP.

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Differential expression of calbindin in nigral dopaminergic neurons in two mice strains with differential susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Cited by 17 publications

References 51 publications

Role of the endolysosomal system in Parkinson’s disease

Role of the endolysosomal system in Parkinson’s disease

Diabetes, a Contemporary Risk for Parkinson’s Disease: Epidemiological and Cellular Evidences

Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration

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