scholarly journals Cross-talk between LRRK2 and PKA: implication for Parkinson's disease?

2017 ◽  
Vol 45 (1) ◽  
pp. 261-267 ◽  
Author(s):  
Elisa Greggio ◽  
Luigi Bubacco ◽  
Isabella Russo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cross Talk ◽  
Brain Function ◽  
Neuronal Development ◽  
Autosomal Dominant ◽  
Leucine Rich Repeat ◽  
Glia Cells ◽  
Multiple Processes ◽  
Brain Homeostasis

Evidence indicates that leucine-rich repeat kinase 2 (LRRK2) controls multiple processes in neurons and glia cells. Deregulated LRRK2 activity due to gene mutation represents the most common cause of autosomal dominant Parkinson's disease (PD). Protein kinase A (PKA)-mediated signaling is a key regulator of brain function. PKA-dependent pathways play an important role in brain homeostasis, neuronal development, synaptic plasticity, control of microglia activation and inflammation. On the other hand, a decline of PKA signaling was shown to contribute to the progression of several neurodegenerative diseases, including PD. In this review, we will discuss the accumulating evidence linking PKA and LRRK2 in neuron and microglia functions, and offer an overview of the enigmatic cross-talk between these two kinases with molecular and cellular implications.

scholarly journals Genetics and Epigenetics of Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Fabio Coppedè
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Rna ◽  
Autosomal Dominant ◽  
Disease Risk ◽  
Sufficient Evidence ◽  
Recent Application ◽  
Leucine Rich Repeat ◽  
Parkinsonian Syndromes ◽  
Genome Wide

In 1997 a mutation in thea-synuclein(SNCA) gene was associated with familial autosomal dominant Parkinson’s disease (PD). Since then, several loci (PARK1-15) and genes have been linked to familial forms of the disease. There is now sufficient evidence that six of the so far identified genes at PARK loci (a-synuclein, leucine-rich repeat kinase 2, parkin, PTEN-induced putative kinase 1, DJ-1, andATP13A2) cause inherited forms of typical PD or parkinsonian syndromes. Other genes at non-PARK loci (MAPT, SCA1, SCA2, spatacsin, POLG1) cause syndromes with parkinsonism as one of the symptoms. The majority of PD cases are however sporadic “idiopathic” forms, and the recent application of genome-wide screening revealed almost 20 genes that might contribute to disease risk. In addition, increasing evidence suggests that epigenetic mechanisms, such as DNA methylation, histone modifications, and small RNA-mediated mechanisms, could regulate the expression of PD-related genes.

scholarly journals The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research

2016 ◽  
Vol 473 (3) ◽  
pp. 221-232 ◽  
Author(s):  
Rebekah G. Langston ◽  
Iakov N. Rudenko ◽  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Autosomal Dominant ◽  
Disease Gene ◽  
Late Onset ◽  
Biochemical Properties ◽  
Leucine Rich Repeat ◽  
Causal Gene ◽  
Preclinical Research

In the period since LRRK2 (leucine-rich repeat kinase 2) was identified as a causal gene for late-onset autosomal dominant parkinsonism, a great deal of work has been aimed at understanding whether the LRRK2 protein might be a druggable target for Parkinson's disease (PD). As part of this effort, animal models have been developed to explore both the normal and the pathophysiological roles of LRRK2. However, LRRK2 is part of a wider family of proteins whose functions in different organisms remain poorly understood. In this review, we compare the information available on biochemical properties of LRRK2 homologues and orthologues from different species from invertebrates (e.g. Caenorhabditis elegans and Drosophila melanogaster) to mammals. We particularly discuss the mammalian LRRK2 homologue, LRRK1, and those species where there is only a single LRRK homologue, discussing examples where each of the LRRK family of proteins has distinct properties as well as those cases where there appear to be functional redundancy. We conclude that uncovering the function of LRRK2 orthologues will help to elucidate the key properties of human LRRK2 as well as to improve understanding of the suitability of different animal models for investigation of LRRK2-related PD.

Leucine-rich repeat kinase 2-related functions in GLIA: an update of the last years

2021 ◽  
Author(s):  
Alice Filippini ◽  
Massimo Gennarelli ◽  
Isabella Russo
Keyword(s):  
Gene Mutation ◽  
Cross Talk ◽  
Immune Cells ◽  
Autosomal Dominant ◽  
Missense Mutations ◽  
Leucine Rich Repeat ◽  
Common Cause ◽  
The Past ◽  
Multiple Processes ◽  
Lrrk2 Gene

Missense mutations in the leucine-rich repeat kinase-2 (LRRK2) gene represent the most common cause of autosomal dominant Parkinson's disease (PD). In the years LRRK2 has been associated with several organelles and related pathways in cell. However, despite the significant amount of research done in the past decade, the contribution of LRRK2 mutations to PD pathogenesis remains unknown. Growing evidence highlights that LRRK2 controls multiple processes in brain immune cells, microglia and astrocytes, and suggests that deregulated LRRK2 activity in these cells, due to gene mutation, might be directly associated with pathological mechanisms underlying PD. In this brief review, we recapitulate and update the last LRRK2 functions dissected in microglia and astrocytes. Moreover, we discuss how dysfunctions of LRRK2-related pathways may impact glia physiology and their cross-talk with neurons, thus leading to neurodegeneration and progression of PD.

A frequent gene mutation associated with autosomal dominant Parkinson's disease

The Lancet ◽  
2005 ◽  
Vol 365 (9457) ◽  
pp. 412-415 ◽  
Author(s):  
A DIFONZO ◽  
C ROHE ◽  
J FERREIRA ◽  
H CHIEN ◽  
L VACCA ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Mutation ◽  
Autosomal Dominant

scholarly journals Therapeutic Potential of α-Synuclein Evolvability for Autosomal Recessive Parkinson’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jianshe Wei ◽  
Gilbert Ho ◽  
Yoshiki Takamatsu ◽  
Eliezer Masliah ◽  
Makoto Hashimoto
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Therapeutic Potential ◽  
Gene Mutations ◽  
Mitochondrial Alteration ◽  
Rational Therapy ◽  
Ubiquitin Proteasome ◽  
Dominant Genes

The majority of Parkinson’s disease (PD) is sporadic in elderly and is characterized by α-synuclein (αS) aggregation and other alterations involving mitochondria, ubiquitin-proteasome, and autophagy. The remaining are familial PD associated with gene mutations of either autosomal dominant or recessive inheritances. However, the former ones are similar to sporadic PD, and the latter ones are accompanied by impaired mitophagy during the reproductive stage. Since no radical therapies are available for PD, the objective of this paper is to discuss a mechanistic role for amyloidogenic evolvability, a putative physiological function of αS, among PD subtypes, and the potential relevance to therapy. Presumably, αS evolvability might benefit familial PD due to autosomal dominant genes and also sporadic PD during reproduction, which may manifest as neurodegenerative diseases through antagonistic pleiotropy mechanism in aging. Indeed, there are some reports describing that αS prevents apoptosis and mitochondrial alteration under the oxidative stress conditions, notwithstanding myriads of papers on the neuropathology of αS. Importantly, β-synuclein (βS), the nonamyloidogenic homologue of αS, might buffer against evolvability of αS protofibrils associated with neurotoxicity. Finally, it is intriguing to predict that increased αS evolvability through suppression of βS expression might protect against autosomal recessive PD. Collectively, further studies are warranted to better understand αS evolvability in PD pathogenesis, leading to rational therapy development.

scholarly journals Effect of a Leucine-rich Repeat Kinase 2 Variant on Motor and Non-motor Symptoms in Chinese Parkinson’s Disease Patients

2016 ◽  
Vol 7 (3) ◽  
pp. 230 ◽  
Author(s):  
Qian Sun ◽  
Tian Wang ◽  
Tian-Fang Jiang ◽  
Pei Huang ◽  
Dun-Hui Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Symptoms ◽  
Leucine Rich Repeat ◽  
Non Motor Symptoms

DEVELOPMENT OF THERAPEUTIC BRAIN STIMULATION TECHNIQUES WITH METHODS FROM NONLINEAR DYNAMICS AND STATISTICAL PHYSICS

2006 ◽  
Vol 16 (07) ◽  
pp. 1889-1911 ◽  
Author(s):  
PETER A. TASS ◽  
CHRISTIAN HAUPTMANN ◽  
OLEKSANDR V. POPOVYCH
Keyword(s):  
Nonlinear Dynamics ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Essential Tremor ◽  
Brain Stimulation ◽  
Brain Function ◽  
Statistical Physics ◽  
Delayed Feedback ◽  
Phase Resetting ◽  
Feedback Mechanisms

Synchronization processes may severely impair brain function, for instance, in Parkinson's disease, essential tremor or epilepsies. We present three different effectively desynchronizing stimulation techniques which have been developed with methods from nonlinear dynamics and statistical physics. These techniques exploit either stochastic phase resetting principles or complex delayed feedback mechanisms. We explain how these methods work and how they can be applied to therapeutic brain stimulation.

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