Neurodegenerative diseases: model organisms, pathology and autophagy

Suresh, Shwetha; Verma, Vijaya; Sateesh, Shruthi; Clement, James P.; Manjithaya, Ravi

doi:10.1007/s12041-018-0955-3

Cited by 17 publications

(22 citation statements)

References 271 publications

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“…Neurons need to constantly maintain homeostasis by preserving healthy organelles and functional proteins, while selectively capturing and eliminating damaged organelles and misfolded proteins. Autophagy, an integral component of the E‐L system, is an intracellular proteostasis pathway that performs this housekeeping function (Mizushima et al ; Nixon ; Suresh et al ) (Fig. A, ).…”

Section: Autophagy In Pd; Cause and Effect Hand In Handmentioning

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: Autophagy In Pd; Cause and Effect Hand In Handmentioning

confidence: 99%

Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

116

105

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“…Given the fundamental role of proteostatic mechanisms in ensuring viability in long-living and post-mitotic cells, it is not surprising that impairment of UPS or autophagy is associated with cognitive decline and neuronal death. In particular, AD, PD, ALS, polyglutaminopathies, and other less common forms of CNS amyloidosis display aggregation of misfolded proteins that can be found as extracellular deposits or intracellular inclusion bodies and aggresomes [59,60]. It should be made clear, however, that the presence of increased autophagosomes in association with misfolded aggregates is not proof of the consequentiality of these conditions, since it does not distinguish whether autophagy imbalance (i.e., increased autophagosome content) is the cause or the effect of protein aggregation.…”

Section: Cytoplasmic Homeostasis and Neuronal Survival: Loss Of Aumentioning

confidence: 99%

Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity

Thellung

Corsaro

Nizzari

et al. 2019

IJMS

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The aim of this review is to critically analyze promises and limitations of pharmacological inducers of autophagy against protein misfolding-associated neurodegeneration. Effective therapies against neurodegenerative disorders can be developed by regulating the “self-defense” equipment of neurons, such as autophagy. Through the degradation and recycling of the intracellular content, autophagy promotes neuron survival in conditions of trophic factor deprivation, oxidative stress, mitochondrial and lysosomal damage, or accumulation of misfolded proteins. Autophagy involves the activation of self-digestive pathways, which is different for dynamics (macro, micro and chaperone-mediated autophagy), or degraded material (mitophagy, lysophagy, aggrephagy). All neurodegenerative disorders share common pathogenic mechanisms, including the impairment of autophagic flux, which causes the inability to remove the neurotoxic oligomers of misfolded proteins. Pharmacological activation of autophagy is typically achieved by blocking the kinase activity of mammalian target of rapamycin (mTOR) enzymatic complex 1 (mTORC1), removing its autophagy suppressor activity observed under physiological conditions; acting in this way, rapamycin provided the first proof of principle that pharmacological autophagy enhancement can induce neuroprotection through the facilitation of oligomers’ clearance. The demand for effective disease-modifying strategies against neurodegenerative disorders is currently stimulating the development of a wide number of novel molecules, as well as the re-evaluation of old drugs for their pro-autophagic potential.

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“…In PD, the continuous aggregate formation leads to an intracellular defect wherein proteostasis regulating mechanisms such as chaperones, Ubiquitin Proteasome System (UPS) and macroautophagy (henceforth autophagy) are impaired, leading to neuronal death [5]. Proof-of-principle experiments have demonstrated that clearing α-synuclein aggregates is beneficial and cytoprotective [6], [7], [8].…”

Section: Introductionmentioning

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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Neurodegenerative diseases: model organisms, pathology and autophagy

Cited by 17 publications

References 271 publications

Role of the endolysosomal system in Parkinson’s disease

Role of the endolysosomal system in Parkinson’s disease

Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity

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

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