scholarly journals Back to the future: new target-validated Rab antibodies for evaluating LRRK2 signalling in cell biology and Parkinson's disease

2018 ◽  
Vol 475 (1) ◽  
pp. 185-189 ◽  
Author(s):  
Patrick A. Eyers
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Biology ◽  
Human Neutrophils ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Biochemical Journal ◽  
The Future ◽  
Brain Extracts ◽  
Sporadic Cases

The addition of phosphate groups to substrates allows protein kinases to regulate a myriad of biological processes, and contextual analysis of protein-bound phosphate is important for understanding how kinases contribute to physiology and disease. Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase linked to familial and sporadic cases of Parkinson's disease (PD). Recent work established that multiple Rab GTPases are physiological substrates of LRRK2, with Rab10 in particular emerging as a human substrate whose site-specific phosphorylation mirrors hyperactive LRRK2 lesions associated with PD. However, current assays to quantify Rab10 phosphorylation are expensive, time-consuming and technically challenging. In back-to-back studies reported in the Biochemical Journal, Alessi and colleagues teamed up with clinical colleagues and collaborators at the Michael J. Fox Foundation (MJFF) for Parkinson's research to develop, and validate, a panel of exquisitely sensitive phospho-specific Rab antibodies. Of particular interest, the monoclonal antibody-designated MJFF-pRAB10 detects phosphorylated Rab 10 on Thr73 in a variety of cells, brain extracts, PD-derived samples and human neutrophils, the latter representing a previously unrecognised biological resource for LRRK2 signalling analysis. In the future, these antibodies could become universal resources in the fight to understand and quantify connections between LRRK2 and Rab proteins, including those associated with clinical PD.

scholarly journals PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Kerryn Berndsen ◽  
Pawel Lis ◽  
Wondwossen M Yeshaw ◽  
Paulina S Wawro ◽  
Raja S Nirujogi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Phosphatase ◽  
Primary Cilia ◽  
A549 Cells ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Biochemical Studies ◽  
Cilia Formation ◽  
Human A549

Mutations that activate LRRK2 protein kinase cause Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all human protein phosphatases revealed that a poorly studied protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins. PPM1H knockout increased endogenous Rab phosphorylation and inhibited Rab dephosphorylation in human A549 cells. Overexpression of PPM1H suppressed LRRK2-mediated Rab phosphorylation. PPM1H also efficiently and directly dephosphorylated Rab8A in biochemical studies. A “substrate-trapping” PPM1H mutant (Asp288Ala) binds with high affinity to endogenous, LRRK2-phosphorylated Rab proteins, thereby blocking dephosphorylation seen upon addition of LRRK2 inhibitors. PPM1H is localized to the Golgi and its knockdown suppresses primary cilia formation, similar to pathogenic LRRK2. Thus, PPM1H acts as a key modulator of LRRK2 signaling by controlling dephosphorylation of Rab proteins. PPM1H activity enhancers could offer a new therapeutic approach to prevent or treat Parkinson’s disease.

scholarly journals The Cell Biology of LRRK2 in Parkinson’s Disease

2021 ◽  
Author(s):  
Ahsan Usmani ◽  
Farbod Shavarebi ◽  
Annie Hiniker
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Biology ◽  
Kinase Inhibitor ◽  
Genetic Model ◽  
Point Mutations ◽  
Model Systems ◽  
Rab Gtpases ◽  
Recent Developments ◽  
Lrrk2 Kinase

Point mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD) and are implicated in a significant portion of apparently sporadic PD. Clinically, LRRK2-driven PD is indistinguishable from sporadic PD, making it an attractive genetic model for the much more common sporadic PD. In this review, we highlight recent advances in understanding LRRK2's subcellular functions using LRRK2-PD models, while also considering some of the limitations of these model systems. Recent developments of particular importance include new evidence of key LRRK2 functions in the endolysosomal system and LRRK2’s regulation of and by Rab GTPases. Additionally, LRRK2's interaction with the cytoskeleton allowed elucidation of the LRRK2 structure and appears relevant to LRRK2 protein degradation and LRRK2 kinase inhibitor therapies. We further discuss how LRRK2's interactions with other PD-driving genes, such as VPS35, GCase, and α-synuclein, may highlight cellular pathways more broadly disrupted in PD.

scholarly journals PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins

2019 ◽  
Author(s):  
Kerryn Berndsen ◽  
Pawel Lis ◽  
Wondwossen Yeshaw ◽  
Paulina S. Wawro ◽  
Raja S. Nirujogi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Phosphatase ◽  
Primary Cilia ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Knock Out ◽  
High Affinity ◽  
Biochemical Studies ◽  
Cilia Formation

AbstractMutations that activate LRRK2 protein kinase cause Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all protein phosphatases revealed that a poorly studied protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins. PPM1H knock out increased endogenous Rab phosphorylation and inhibited Rab dephosphorylation. Overexpression of PPM1H suppressed LRRK2-mediated Rab phosphorylation. PPM1H also efficiently and directly dephosphorylated Rab8A in biochemical studies. A “substrate-trapping” PPM1H mutant (Asp288Ala) binds with high affinity to endogenous, LRRK2-phosphorylated Rab proteins, thereby blocking dephosphorylation seen upon addition of LRRK2 inhibitors. PPM1H is localized to the Golgi and its knockdown suppresses primary cilia formation, similar to pathogenic LRRK2. Thus, PPM1H acts as a key modulator of LRRK2 signaling by controlling dephosphorylation of Rab proteins. PPM1H activity enhancers could offer a new therapeutic approach to prevent or treat Parkinson’s disease.

Molecular imaging of gene therapy. The future in Parkinson's disease therapy?

2005 ◽  
Vol 32 (S 4) ◽  
Author(s):  
A.H Jacobs ◽  
R Hilker ◽  
L Burghaus ◽  
W.D Heiss
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Molecular Imaging ◽  
Disease Therapy ◽  
The Future

scholarly journals Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

2021 ◽  
pp. 1-16
Author(s):  
Alison Fellgett ◽  
C. Adam Middleton ◽  
Jack Munns ◽  
Chris Ugbode ◽  
David Jaciuch ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Genetic Interaction ◽  
In Vitro Assays ◽  
Rab Proteins ◽  
Circadian Activity ◽  
Loss Of Function ◽  
Lrrk2 G2019s

Background: Inherited mutations in the LRRK2 protein are the common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.

scholarly journals The Future of Brain Imaging in Parkinson’s Disease

2018 ◽  
Vol 8 (s1) ◽  
pp. S47-S51 ◽  
Author(s):  
Rick C. Helmich ◽  
David E. Vaillancourt ◽  
David J. Brooks
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Brain Imaging ◽  
The Future

scholarly journals The Future of GDNF in Parkinson's Disease

2020 ◽  
Vol 12 ◽  
Author(s):  
Fredric P. Manfredsson ◽  
Nicole K. Polinski ◽  
Thyagarajan Subramanian ◽  
Nicholas Boulis ◽  
Dustin R. Wakeman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
The Future

The future of cell therapies in the treatment of Parkinson's disease

2007 ◽  
Vol 7 (10) ◽  
pp. 1487-1498 ◽  
Author(s):  
Rocio Laguna Goya ◽  
Wei-Li Kuan ◽  
Roger A Barker
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Therapies ◽  
The Future

scholarly journals Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

2020 ◽  
Vol 91 (1) ◽  
Author(s):  
Mikko Airavaara ◽  
Ilmari Parkkinen ◽  
Julia Konovalova ◽  
Katrina Albert ◽  
Piotr Chmielarz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Models ◽  
The Future
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