A strategy for the generation, characterization and distribution of animal models by The Michael J. Fox Foundation for Parkinson's Research

Baptista, Marco A. S.; Dave, Kuldip D.; Sheth, Niketa P.; Silva, Shehan N. De; Carlson, Kirsten Matoy; Aziz, Yasmin; Fiske, Brian; Sherer, Todd; Frasier, Mark

doi:10.1242/dmm.011940

Cited by 34 publications

(34 citation statements)

References 73 publications

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“…DNA transfections in HEK293T cells were performed with the calcium phosphate method and Lipofectamine2000 (ThermoFisher Scientific) or GenJet (SignaGen Laboratories) were used for transfections in HeLa cells. Immunocytochemistry was done on fibroblasts of Long Evans wild-type or Long Evans or PINK1 −/− rats (47). Rat and mouse hippocampal neurons were isolated according to standard procedures and cultured as in ref.…”

Section: Methodsmentioning

confidence: 99%

“…Parkin-YFP signal colocalizes with α-Tom20 signal in the reconstruction and in the line-scan. Because Parkin recruitment to mitochondria is thought to depend on its activation by PINK1 (35), we also examined the effects of MiroS156E expression in primary embryonic fibroblasts from PINK1 −/− rats (47). MiroS156E caused equivalent mitochondrial localization of YFP-Parkin in these cells (Fig.…”

Section: Phosphomimetic Mutant Miros156e Enhances the Recruitment Ofmentioning

confidence: 99%

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Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

119

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The PTEN-induced putative kinase 1 (PINK1)/Parkin pathway can tag damaged mitochondria and trigger their degradation by mitophagy. Before the onset of mitophagy, the pathway blocks mitochondrial motility by causing Miro degradation. PINK1 activates Parkin by phosphorylating both Parkin and ubiquitin. PINK1, however, has other mitochondrial substrates, including Miro (also called RhoT1 and -2), although the significance of those substrates is less clear. We show that mimicking PINK1 phosphorylation of Miro on S156 promoted the interaction of Parkin with Miro, stimulated Miro ubiquitination and degradation, recruited Parkin to the mitochondria, and via Parkin arrested axonal transport of mitochondria. Although Miro S156E promoted Parkin recruitment it was insufficient to trigger mitophagy in the absence of broader PINK1 action. In contrast, mimicking phosphorylation of Miro on T298/T299 inhibited PINK1-induced Miro ubiquitination, Parkin recruitment, and Parkin-dependent mitochondrial arrest. The effects of the T298E/T299E phosphomimetic were dominant over S156E substitution. We propose that the status of Miro phosphorylation influences the decision to undergo Parkin-dependent mitochondrial arrest, which, in the context of PINK1 action on other substrates, can restrict mitochondrial dynamics before mitophagy.is the second most common neurodegenerative disorder, and is closely linked to mitochondrial dysfunction (1, 2). Two hereditary forms of recessive PD are caused by mutations in PINK1 (PTEN-induced putative kinase 1), a Ser/Thr mitochondrial kinase, and Parkin, a cytosolic E3 ubiquitin ligase (3, 4). The realization that these proteins are in a single pathway, with PINK1 acting upstream of Parkin to influence mitochondrial properties, was a critical step in uncovering the underlying pathological mechanisms of PD (5-7). This pathway can trigger the selective autophagy of damaged mitochondria, termed mitophagy (8, 9), but additional cellular functions have also been indicated for PINK1 and Parkin (10-15). Much, however, remains unclear about how the PINK1/Parkin pathway is regulated.In current models of PINK1/Parkin mitophagy (reviewed in ref. 1), healthy mitochondria import a PINK1 precursor constitutively to the inner membrane, where it is cleaved (16-18). The cleaved form then returns to the cytoplasm and is degraded by the N-end rule pathway (19). Mitochondrial depolarization, or protein misfolding in the matrix of energized mitochondria (20), prevent the import and degradation of PINK1, resulting in the accumulation of PINK1 on the outer mitochondrial membrane (OMM) (9,21,22). Once on the OMM, PINK1 kinase activity recruits Parkin from the cytosol (8, 9). Although Parkin adopts a self-inhibited conformation in solution (23-25), it becomes fully activated in a PINK1-dependent manner on the mitochondria (9, 21). Parkin ubiquitinates numerous proteins of the OMM (26, 27), and thereby recruits autophagy-related proteins to the damaged mitochondrion for autophagosome assembly (28-30).How PINK1 recruits and activa...

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Section: Methodsmentioning

confidence: 99%

Section: Phosphomimetic Mutant Miros156e Enhances the Recruitment Ofmentioning

confidence: 99%

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

119

View full text Add to dashboard Cite

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“…Twelve male Long-Evans rats with a homozygous knockout of PINK1 (SAGE ™ Research Labs, Boyertown, PA, USA[38]), aged 5 weeks at the time of pre-study habituation, and female wildtype stimulus rats ( n = 6) were housed in same-sex groups of two in standard polycarbonate cages with sawdust bedding on a reversed 12:12 hour light: dark cycle. Male PINK1 −/− rats were randomly divided into two groups, vocal exercise-trained and sham-trained.…”

Section: Methodsmentioning

confidence: 99%

Exercise Effects on Early Vocal Ultrasonic Communication Dysfunction in a PINK1 Knockout Model of Parkinson’s Disease

Kelm‐Nelson

Yang

Ciucci

2015

JPD

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Background Parkinson’s disease (PD) is a complex neurodegenerative disease with vocal communication deficits that manifest early, progress, and are largely resistant to medical interventions; however, they do respond to exercise-based speech and voice therapies. Objective and Methods To study how exercise-based vocal treatment can affect the progression of communication deficits related to PD, we studied ultrasonic vocalizations (USVs) in rats with homozygous knockout (−/−) of PINK1, a gene mutation known to cause PD, under the manipulation of a behavioral vocal exercise paradigm that allows us to precisely control dose and timing of exercise in the prodromal (prior to diagnosis) stages. Results We show that intensive vocal-training rescues frequency range and intensity deficits as well as leads to an increase in call complexity and duration of calls compared to sham-training; however, over time this training regime loses significant effect as the disease progresses. We also show effects of frequent handling and conspecific (male-female) interaction in the sham-training group as they demonstrated significantly higher call rate, intensity, frequency range, and call complexity compared to rats without any form of training and consequently less handling/interaction. Further, we confirm that this model exhibits progressive gross motor deficits that indicate neurodegeneration. Discussion This study suggests that the evolving nature of vocal communication deficits requires an adjustment of therapy targets and more intensive training over the course of this progressive disease and demonstrates the importance of frequent social experiences.

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“…Similarly, symptoms of motor impairment, such as muscle weakness and dystonia, are evident in LRRK2 transgenic mice [74]. However, LRRK2 mutant animal models do not exhibit all the hallmarks of PD, such as Lewy bodies or DA neuron loss [75]. Moreover, the introduction of viral vectors has been proven to induce inflammatory responses and toxicity [73].…”

Section: Lrrk2 As a Therapeutic Targetmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Chen¹,

Chen²,

Pu³

2018

Eur Neurol

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Background: Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. Summary: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment. In this review, we discuss the role of LRRK2 in PD and recent progress in the use of LRRK2 inhibitors as therapeutic agents. Key Messages: LRRK2 plays a significant role in the pathophysiology of PD, and pharmacological inhibition of LRRK2 has become one of the most promising potential therapies for PD. Further research is warranted to determine the functions of LRRK2 and expand the applications of LRRK2 inhibitors in PD treatment.

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A strategy for the generation, characterization and distribution of animal models by The Michael J. Fox Foundation for Parkinson's Research

Cited by 34 publications

References 73 publications

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Exercise Effects on Early Vocal Ultrasonic Communication Dysfunction in a PINK1 Knockout Model of Parkinson’s Disease

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

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