The sound of movement,a noninvasive surgical procedure for treating Parkinson’s disease

Parkinson’s disease(PD)is the second most common degenerative neurological disorder after Alzheimer’s disease.As one of fastest growing neurological conditions,PD affects millions of elderly people worldwide.PD patients display progressive motor symptoms,including resting tremor,slowed movement,impaired posture and balance,and rigid muscles[1].Additionally,they also often suffer from chronic pain,depression,dementia,and other non-motor symptoms[2].Medications and surgery can improve patient’s motor performance to some degree,while the treatment for non-motor conditions is limited.Moreover,long-term medication can cause severe side effects,such as dyskinesia and impulse control disorders[3,4].Therefore,new mechanistic insights and therapeutic agents/procedures are still needed to improve the treatment of increasing number of PD patients.

No apparent transmission of transgenic α–synuclein into nigrostriatal dopaminergic neurons in multiple mouse models

Background:α–synuclein(α–syn)is the main component of intracytoplasmic inclusions deposited in the brains of patients with Parkinson’s disease(PD)and certain other neurodegenerative disorders.Recent studies have explored the ability ofα–syn to propagate between or across neighboring neurons and supposedly“infect”them with a prion–like mechanism.However,much of this research has used stereotaxic injections of heterologousα–syn fibrils to induce the spreading of inclusions in the rodent brains.Whetherα–syn is able to transmit from the host cells to their neighboring cells in vivo is unclear.Methods:Using immunestaining,we examined the potential propagation ofα–syn into nigrostriatal dopaminergic(DA)neurons in three lines of transgenic mice that overexpress human wild–typeα–syn(hα–syn)in different neuron populations.Results:After testing for three different routes by which hα–syn propagation might occur,we were unable to find any evidence that hα–syn behaved like a prion and could be transmitted overtime into the DA neurons initially lack of hα–syn expression.Conclusions:In transgenic mice hα–syn does not have the ability to propagate at pathologically significant levels between or across neurons.It must be noted that these observations do not disprove the studies that show its prion–like qualities,but rather that propagation is not detectable in transgenic models that do not use any injections of heterologous proteins or viral vectors to induce a spreading state.

AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression

Background:Leucine-rich repeat kinase 2(LRRK2)mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease(PD).Especially,LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD.Advanced glycation end products(AGEs)are produced in high amounts in diabetes and diverse aging-related disorders,such as cardiovascular disease,renal disease,and neurological disease.AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death.RAGE,receptor of AGEs,is activated by interaction with AGEs and mediates AGE-induced cytotoxicity.Whether AGE and RAGE are involved in the pathogenesis of mutant LRRK2 is unknown.Methods:Using cell lines transfected with mutant LRRK2 as well as primary neuronal cultures derived from LRRK2 wild-type(WT)and G2019S transgenic mice,we compared the impact of AGE treatment on the survival of control and mutant cells by immunostaining.We also examined the levels of RAGE proteins in the brains of transgenic mice and PD patients by western blots.Results:We show that LRRK2 G2019S mutant-expressing neurons were more sensitive to AGE-induced cell death compared to controls.Furthermore,we found that the levels of RAGE proteins were upregulated in LRRK2 G2019S mutant cells.Conclusions:These data suggest that enhanced AGE-RAGE interaction contributes to LRRK2 G2019S mutation-mediated progressive neuronal loss in PD.

Aldehyde Dehydrogenase 1 making molecular inroads into the differential vulnerability of nigrostriatal dopaminergic neuron subtypes in Parkinson’s disease

A preferential dysfunction/loss of dopaminergic(DA)neurons in the substantia nigra pars compacta(SNpc)accounts for the main motor symptoms of Parkinson’s disease(PD),the most common degenerative movement disorder.However,the neuronal loss is not stochastic,but rather displays regionally selectivity,indicating the existence of different DA subpopulations in the SNpc.To identify the underlying molecular determinants is thereby instrumental in understanding the pathophysiological mechanisms of PD-related neuron dysfunction/loss and offering new therapeutic targets.Recently,we have demonstrated that aldehyde dehydrogenase 1(ALDH1A1)is one such molecular determinant that defines and protects an SNpc DA neuron subpopulation preferentially affected in PD.In this review,we provide further analysis and discussion on the roles of ALDH1A1 in the function and survival of SNpc DA neurons in both rodent and human brains.We also explore the feasibility of ALDH1A1 as a potential biomarker and therapeutic target for PD.

Opioid system in L-DOPA-induced dyskinesia

L-3,4-Dihydroxyphenylalanine(L-DOPA)-induced dyskinesia(LID)is a major clinical complication in the treatment of Parkinson’s disease(PD).This debilitating side effect likely reflects aberrant compensatory responses for a combination of dopaminergic neuron denervation and repeated L-DOPA administration.Abnormal endogenous opioid signal transduction pathways in basal ganglia have been well documented in LID.Opioid receptors have been targeted to alleviate the dyskinesia.However,the exact role of this altered opioid activity is remains under active investigation.In the present review,we discuss the current understanding of opioid signal transduction in the basal ganglia and how the malfunction of opioid signaling contributes to the pathophysiology of LID.Further study of the opioid system in LID may lead to new therapeutic targets and improved treatment of PD patients.