LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity

Karuppagounder, Senthilkumar S.; Xiong, Yulan; Lee, Yong Kyu; Lawless, Maeve C.; Kim, Dong-Hyun; Nordquist, Emily; Martin, Ian; Ge, Preston; Brahmachari, Saurav; Jhaldiyal, Aanishaa; Kumar, Manoj; Andrabi, Shaida A.; Dawson, Ted M.; Dawson, Valina L.

doi:10.1016/j.jchemneu.2016.01.007

Cited by 39 publications

(37 citation statements)

References 42 publications

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“…While α‐syn null mice are protected against MPTP toxicity, and tg mice overexpressing human α‐syn may be more sensitive to MPTP‐induced toxicity (Dauer et al., ; Klivenyi et al., ; Song, Shults, Sisk, Rockenstein, & Masliah, ), LRRK2 knockout mice do not appear protected from MPTP (Andres‐Mateos et al., ). However, mice overexpressing G2019S‐LRRK2 appear more sensitive to MPTP (Karuppagounder et al., ). Thus, at least through MPTP, both α‐syn and LRRK2 appear to have a functional role in mitochondria‐dysfunction that can cause neurodegeneration.…”

Section: Rationale For a Meaningful Interaction Between Lrrk2 And α‐Smentioning

confidence: 99%

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

Cresto

Gardier

Gubinelli

et al. 2018

Eur J of Neuroscience

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Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α‐synuclein and LRRK2 pathogenic mutations. While α‐synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual‐enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α‐synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α‐synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14‐3‐3s that may regulate α‐synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α‐synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD.

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Section: Rationale For a Meaningful Interaction Between Lrrk2 And α‐Smentioning

confidence: 99%

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

Cresto

Gardier

Gubinelli

et al. 2018

Eur J of Neuroscience

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“…Consistently, when these mice are exposed to parkinsonian toxins, they do show enhanced susceptibility to nigrostriatal degeneration. Thus, Daher et al (2015) reported that G2019S transgenic rats were more prone than wild-type rats to develop nigrostriatal dopaminergic degeneration after AAVmediated α-syn overexpression, whereas Karuppagounder et al (2016) showed that G2019S transgenic mice were more sensitive to acute MPTP toxicity. Interestingly, subchronic administration of the second-generation LRRK2 kinase inhibitor PF-06447475 (West, 2017) reversed the neurotoxicity of α-syn overexpression not only in G2019S transgenic but also in wild-type rats.…”

Section: Are Alp Changes Observed In Lrrk2 Models Relevant For Lrrk2-mentioning

confidence: 99%

Autophagy and LRRK2 in the Aging Brain

2019

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Autophagy is a highly conserved process by which long-lived macromolecules, protein aggregates and dysfunctional/damaged organelles are delivered to lysosomes for degradation. Autophagy plays a crucial role in regulating protein quality control and cell homeostasis in response to energetic needs and environmental challenges. Indeed, activation of autophagy increases the lifespan of living organisms, and impairment of autophagy is associated with several human disorders, among which neurodegenerative disorders of aging, such as Parkinson's disease. These disorders are characterized by the accumulation of aggregates of aberrant or misfolded proteins that are toxic for neurons. Since aging is associated with impaired autophagy, autophagy inducers have been viewed as a strategy to counteract the age-related physiological decline in brain functions and emergence of neurodegenerative disorders. Parkinson's disease is a hypokinetic, multisystemic disorder characterized by agerelated, progressive degeneration of central and peripheral neuronal populations, associated with intraneuronal accumulation of proteinaceous aggregates mainly composed by the presynaptic protein α-synuclein. α-synuclein is a substrate of macroautophagy and chaperone-mediated autophagy (two major forms of autophagy), thus impairment of its clearance might favor the process of α-synuclein seeding and spreading that trigger and sustain the progression of this disorder. Genetic factors causing Parkinson's disease have been identified, among which mutations in the LRRK2 gene, which encodes for a multidomain protein encompassing central GTPase and kinase domains, surrounded by protein-protein interaction domains. Six LRRK2 mutations have been pathogenically linked to Parkinson's disease, the most frequent being the G2019S in the kinase domain. LRRK2-associated Parkinson's disease is clinically and neuropathologically similar to idiopathic Parkinson's disease, also showing age-dependency and incomplete penetrance. Several mechanisms have been proposed through which LRRK2 mutations can lead to Parkinson's disease. The present article will focus on the evidence that LRRK2 and its mutants are associated with autophagy dysregulation. Studies in cell lines and neurons in vitro and in LRRK2 knockout , knock-in, kinase-dead and transgenic animals in vivo will be reviewed. The role of aging in LRRK2-induced synucleinopathy will be discussed. Possible mechanisms underlying the LRRK2-mediated control over autophagy will be analyzed, and the contribution of autophagy dysregulation to the neurotoxic actions of LRRK2 will be examined.

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“…While PTMs serve to facilitate the normal functions of α-synuclein and LRRK2 in the healthy brain [6, 7], abnormal modifications may be associated with PD pathogenesis. Additionally, environmental toxicants such as rotenone, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and manganese (Mn) have been shown to interact with α - synuclein and LRRK2 and cause pathogenesis [8, 9]. Mn is particularly of interest since chronic exposure to Mn causes a neurological disorder resembling idiopathic PD, referred to as manganism [10].…”

Section: Introductionmentioning

confidence: 99%

The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

Pajarillo

Rizor

Lee

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD), and the most prevalent movement disorder. PD is characterized by dopaminergic neurodegeneration in the substantia nigra, but its etiology has yet to be established. Among several genetic variants contributing to PD pathogenesis, α-synuclein and leucine-rich repeat kinase (LRRK2) are widely associated with neuropathological phenotypes in familial and sporadic PD. α-Synuclein and LRRK2 found in Lewy bodies, a pathogenetic hallmark of PD, are often posttranslationally modified. As posttranslational modifications (PTMs) are key processes in regulating the stability, localization, and function of proteins, PTMs have emerged as important modulators of pathogenic mechanisms of α-synuclein and LRRK2. Aberrant PTMs altering phosphorylation, ubiquitination, nitration and truncation of these proteins promote PD pathogenesis, while other PTMs such as sumoylation may be protective. Although the causes of many aberrant PTMs are unknown, environmental risk factors may contribute to their aberrancy. Environmental toxicants such as rotenone and paraquat have been shown to interact with these proteins and promote their abnormal PTMs. Notably, manganese (Mn) exposure leads to PD-like neurological disorder referred to as manganism—and induces pathogenic PTMs of α-synuclein and LRRK2. In this review, we highlight the role of PTMs of LRRK2 and α-synuclein in PD pathogenesis and discuss the impact of environmental risk factors on their aberrancy.

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LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity

Cited by 39 publications

References 42 publications

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

Autophagy and LRRK2 in the Aging Brain

The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

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