Parkinson's disease and mitophagy: an emerging role for LRRK2

Current Knowledge ◽

Muscle Stiffness ◽

Common Mutation ◽

Common Denominator

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson’s Disease In Vitro and In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8169125 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Hefeng Zhou ◽

Min Shao ◽

Xuanjun Yang ◽

Chuwen Li ◽

Guozhen Cui ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Motor Coordination ◽

Nerve Fibers ◽

Neuroprotective Effects ◽

6 Hydroxydopamine

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer’s disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.

GRP78/BIP/HSPA5 as a Therapeutic Target in Models of Parkinson’s Disease: A Mini Review

Advances in Pharmacological Sciences ◽

10.1155/2019/2706783 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Adaze Bijou Enogieru ◽

Sylvester Ifeanyi Omoruyi ◽

Donavon Charles Hiss ◽

Okobi Eko Ekpo

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Er Stress ◽

Current Knowledge ◽

Dopamine Neurons ◽

Unfolded Protein ◽

Folded Proteins ◽

The Unfolded Protein Response

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by selective loss of dopamine neurons in the substantia nigra pars compacta of the midbrain. Reports from postmortem studies in the human PD brain, and experimental PD models reveal that endoplasmic reticulum (ER) stress is implicated in the pathogenesis of PD. In times of stress, the unfolded or misfolded proteins overload the folding capacity of the ER to induce a condition generally known as ER stress. During ER stress, cells activate the unfolded protein response (UPR) to handle increasing amounts of abnormal proteins, and recent evidence has demonstrated the activation of the ER chaperone GRP78/BiP (78 kDa glucose-regulated protein/binding immunoglobulin protein), which is important for proper folding of newly synthesized and partly folded proteins to maintain protein homeostasis. Although the activation of this protein is essential for the initiation of the UPR in PD, there are inconsistent reports on its expression in various PD models. Consequently, this review article aims to summarize current knowledge on neuroprotective agents targeting the expression of GRP78/BiP in the regulation of ER stress in experimental PD models.

Unexpected Implication of SRP and AGO2 in Parkinson’s Disease: Involvement in Alpha-Synuclein Biogenesis

Cells ◽

10.3390/cells10102792 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2792

Author(s):

Sarah Hernandez ◽

Elena Tikhonova ◽

Kristen Baca ◽

Fanpeng Zhao ◽

Xiongwei Zhu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Protein Quality ◽

Signal Sequence ◽

Alpha Synuclein ◽

Cytoplasmic Inclusions ◽

Hydrophobic Domain

Parkinson’s disease (PD) is a neurodegenerative disorder classified by the loss of dopaminergic neurons in the substantia nigra pars compacta, the region of the brain that is responsible for motor control. Surviving neurons in this region contain aggregated protein alpha-Synuclein (αSyn) in the form of cytoplasmic inclusions, referred to as Lewy bodies. Changes in αSyn expression are also associated with PD and its progression. Previously, we demonstrated that signal recognition particle (SRP) and Argonaute 2 (AGO2) proteins are involved in protein quality control at the ribosome during translation. We also demonstrated that SRP has an mRNA protection function in addition to a protein targeting function, thus controlling mRNA and protein expression. In this study, we tested involvement of these factors in αSyn biogenesis. We hypothesize that loss of these factors may interfere with αSyn expression, and subsequently, be associated with PD. Using depletion assays in human cell culture and analysis of these proteins in the brains of deceased PD patients, we demonstrate that SRP and AGO2 are involved in the control of αSyn expression and AGO2 has reduced expression in PD. We show for the first time that SRP is involved in mRNA protection of αSyn, a protein that does not have a signal sequence or transmembrane span. Our findings suggest that SRP may interact with a hydrophobic domain in the middle of αSyn during translation. Understanding the molecular mechanisms controlling αSyn biogenesis in cells is vital to developing preventative therapies against PD.

Physiological and pathological functions of LRRK2: implications from substrate proteins

Neuronal Signaling ◽

10.1042/ns20180005 ◽

2018 ◽

Vol 2 (4) ◽

Cited By ~ 4

Author(s):

Miho Araki ◽

Genta Ito ◽

Taisuke Tomita

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Kinase Activity ◽

Lewy Bodies ◽

Motor Dysfunction ◽

Rab Gtpases ◽

Substrate Proteins

Leucine-rich repeat kinase 2 (LRRK2) encodes a 2527-amino acid (aa) protein composed of multiple functional domains, including a Ras of complex proteins (ROC)-type GTP-binding domain, a carboxyl terminal of ROC (COR) domain, a serine/threonine protein kinase domain, and several repeat domains. LRRK2 is genetically involved in the pathogenesis of both sporadic and familial Parkinson’s disease (FPD). Parkinson’s disease (PD) is the second most common neurodegenerative disorder, manifesting progressive motor dysfunction. PD is pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and the presence of intracellular inclusion bodies called Lewy bodies (LB) in the remaining neurons. As the most frequent PD-causing mutation in LRRK2, G2019S, increases the kinase activity of LRRK2, an abnormal increase in LRRK2 kinase activity is believed to contribute to PD pathology; however, the precise biological functions of LRRK2 involved in PD pathogenesis remain unknown. Although biochemical studies have discovered several substrate proteins of LRRK2 including Rab GTPases and tau, little is known about whether excess phosphorylation of these substrates is the cause of the neurodegeneration in PD. In this review, we summarize latest findings regarding the physiological and pathological functions of LRRK2, and discuss the possible molecular mechanisms of neurodegeneration caused by LRRK2 and its substrates.

A Link between Autophagy and the Pathophysiology of LRRK2 in Parkinson's Disease

Parkinson s Disease ◽

10.1155/2012/324521 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Patricia Gómez-Suaga ◽

Elena Fdez ◽

Marian Blanca Ramírez ◽

Sabine Hilfiker

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Enzymatic Activity ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Mutant Gene ◽

Pathogenic Mutation ◽

Kinase Domain ◽

Mutant Lrrk2

Parkinson's disease is a debilitating neurodegenerative disorder, and its molecular etiopathogenesis remains poorly understood. The discovery of monogenic forms has significantly advanced our understanding of the molecular mechanisms underlying PD, as it allows generation of cellular and animal models carrying the mutant gene to define pathological pathways. Mutations in leucine-rich repeat kinase 2 (LRRK2) cause dominantly inherited PD, and variations increase risk, indicating that LRRK2 is an important player in both genetic and sporadic forms of the disease. G2019S, the most prominent pathogenic mutation, maps to the kinase domain and enhances enzymatic activity of LRRK2, which in turn seems to correlate with cytotoxicity. Since kinases are druggable targets, this has raised great hopes that disease-modifying therapies may be developed around modifying LRRK2 enzymatic activity. Apart from cytotoxicity, changes in autophagy have been consistently reported in the context of G2019S mutant LRRK2. Here, we will discuss current knowledge about mechanism(s) by which mutant LRRK2 may regulate autophagy, which highlights additional putative therapeutic targets.

Targeting bone morphogenetic protein signalling in midbrain dopaminergic neurons as a therapeutic approach in Parkinson's disease

Neuronal Signaling ◽

10.1042/ns20170027 ◽

2017 ◽

Vol 1 (2) ◽

Cited By ~ 2

Author(s):

Gerard W. O'Keeffe ◽

Shane V. Hegarty ◽

Aideen M. Sullivan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurotrophic Factors ◽

Neurotrophic Factor ◽

Molecular Mechanisms ◽

Axon Growth ◽

Nervous System Development ◽

Adult Brain ◽

Bmp Receptors

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by the degeneration of midbrain dopaminergic (mDA) neurons and their axons, and aggregation of α-synuclein, which leads to motor and late-stage cognitive impairments. As the motor symptoms of PD are caused by the degeneration of a specific population of mDA neurons, PD lends itself to neurotrophic factor therapy. The goal of this therapy is to apply a neurotrophic factor that can slow down, halt or even reverse the progressive degeneration of mDA neurons. While the best known neurotrophic factors are members of the glial cell line-derived neurotrophic factor (GDNF) family, their lack of clinical efficacy to date means that it is important to continue to study other neurotrophic factors. Bone morphogenetic proteins (BMPs) are naturally secreted proteins that play critical roles during nervous system development and in the adult brain. In this review, we provide an overview of the BMP ligands, BMP receptors (BMPRs) and their intracellular signalling effectors, the Smad proteins. We review the available evidence that BMP–Smad signalling pathways play an endogenous role in mDA neuronal survival in vivo, before outlining how exogenous application of BMPs exerts potent effects on mDA neuron survival and axon growth in vitro and in vivo. We discuss the molecular mechanisms that mediate these effects, before highlighting the potential of targeting the downstream effectors of BMP–Smad signalling as a novel neuroprotective approach to slow or stop the degeneration of mDA neurons in PD.

Combined knockout of Lrrk2 and Rab29 does not result in behavioral abnormalities in vivo

10.1101/2020.05.13.093708 ◽

2020 ◽

Cited By ~ 2

Author(s):

Melissa Conti Mazza ◽

Victoria Nguyen ◽

Alexandra Beilina ◽

Jinhui Ding ◽

Mark R. Cookson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Kinase Activity ◽

Association Studies ◽

Dopamine Neurons ◽

Genome Wide Association Studies ◽

Double Knockout ◽

Knockout Mouse Model

AbstractCoding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.Significance statementGenetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson’s disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson’s disease in vivo

10.1101/2020.12.06.408997 ◽

2020 ◽

Author(s):

Eiji Inoue ◽

Takahiro Suzuki ◽

Yasuharu Shimizu ◽

Keiichi Sudo ◽

Haruhisa Kawasaki ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Life Span ◽

Neuronal Cell ◽

Crocus Sativus ◽

Motor Symptoms ◽

Protective Effects

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in A30P fly PD model in eye. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.

Potential Role of Caffeine in the Treatment of Parkinson’s Disease

The Open Neurology Journal ◽

10.2174/1874205x01610010042 ◽

2016 ◽

Vol 10 (1) ◽

pp. 42-58 ◽

Cited By ~ 8

Author(s):

Mohsin H.K. Roshan ◽

Amos Tambo ◽

Nikolai P. Pace

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Randomized Clinical Trials ◽

Lewy Bodies ◽

Muscle Rigidity ◽

Therapeutic Effects ◽

Motor Symptoms ◽

Wide Range

Parkinson’s disease [PD] is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1% of the population over the age of 55. The underlying neuropathology seen in PD is characterised by progressive loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy bodies. The Lewy bodies are composed of aggregates of α-synuclein. The motor manifestations of PD include a resting tremor, bradykinesia, and muscle rigidity. Currently there is no cure for PD and motor symptoms are treated with a number of drugs including levodopa [L-dopa]. These drugs do not delay progression of the disease and often provide only temporary relief. Their use is often accompanied by severe adverse effects. Emerging evidence from bothin vivoandin vitrostudies suggests that caffeine may reduce parkinsonian motor symptoms by antagonising the adenosine A2Areceptor, which is predominately expressed in the basal ganglia. It is hypothesised that caffeine may increase the excitatory activity in local areas by inhibiting the astrocytic inflammatory processes but evidence remains inconclusive. In addition, the co-administration of caffeine with currently available PD drugs helps to reduce drug tolerance, suggesting that caffeine may be used as an adjuvant in treating PD. In conclusion, caffeine may have a wide range of therapeutic effects which are yet to be explored, and therefore warrants further investigation in randomized clinical trials.

p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease

Journal of Neuroinflammation ◽

10.1186/s12974-021-02349-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Jialong Chen ◽

Kanmin Mao ◽

Honglin Yu ◽

Yue Wen ◽

Hua She ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nlrp3 Inflammasome ◽

Dopaminergic Neurons ◽

Microglia Activation ◽

Microglial Cells ◽

Mice Model ◽

Chaperone Mediated Autophagy

Abstract Background Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies suggested that misfolded α-synuclein induces the inflammatory response and autophagy dysfunction in microglial cells. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the relationship between autophagy deficiency and NLRP3 activation induced by α-synuclein accumulation is not well understood. Methods Through immunoblotting, immunocytochemistry, immunofluorescence, flow cytometry, ELISA and behavioral tests, we investigated the role of p38-TFEB-NLRP3 signaling pathways on neuroinflammation in the α-synuclein A53T PD models. Results Our results showed that increased protein levels of NLRP3, ASC, and caspase-1 in the α-synuclein A53T PD models. P38 is activated by overexpression of α-synuclein A53T mutant, which inhibited the master transcriptional activator of autophagy TFEB. And we found that NLRP3 was degraded by chaperone-mediated autophagy (CMA) in microglial cells. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Inhibition of p38 had a protective effect on Parkinson's disease model via suppressing the activation of NLRP3 inflammasome pathway. Moreover, both p38 inhibitor SB203580 and NLRP3 inhibitor MCC950 not only prevented neurodegeneration in vivo, but also alleviated movement impairment in α-synuclein A53T-tg mice model of Parkinson’s disease. Conclusion Our research reveals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease, which could be a potential therapeutic strategy for PD. Graphical abstract p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease. In this model, p38 activates NLRP3 inflammasome via inhibiting TFEB in microglia. TFEB signaling negatively regulates NLRP3 inflammasome through increasing LAMP2A expression, which binds to NLRP3 and promotes its degradation via chaperone-mediated autophagy (CMA). NLRP3-mediated microglial activation promotes the death of dopaminergic neurons.