Chaperoning glucocerebrosidase:a therapeutic strategy for both Gaucher disease and Parkinsonism

Gaucher disease （GD） is a lysosomal storage disorder （LSD） affecting approximately 1 in 50,000 individuals in the general population. Mutations in both alleles of the GBA1 gene result in deficient glucocerebrosidase （GCase） activity, which in turn leads to the accumulation of glycolipid substrates and impaired lysosomal function. GD is a multisystern disorder with a vast spectrum of clinical phenotvpes,

Cross-talks among GBA mutations,glucocerebrosidase,and a-synuclein in 66/4-associated Parkinson's disease and their targeted therapeutic approaches:a comprehensive review

Current therapies for Parkinson's disease(PD)are palliative,of which the levodopa/carbidopa therapy remains the primary choice but is unable to modulate the progression of neurodegeneration.Due to the complication of such a multifactorial disorder and significant limitations of the therapy,numerous genetic approaches have been proved effective in finding out genes and mechanisms implicated in this disease.Following the observation of a higher frequency of PD in Gaucher's disease(GD),a lysosomal storage condition,mutations of glycosylceramidase beta(GBA)encoding glucocerebrosidase(GCase)have been shown to be involved and have been explored in the context of PD.GBA mutations are the most common genetic risk factor of PD.Various studies have revealed the relationships between PD and GM gene mutations,facilitating a better understanding of this disorder.Various hypotheses delineate that the pathological mutations of GBA minimize the enzymatic activity of GCase,which affects the proliferation and clearance of α-synuclein;this affects the lysosomal homeostasis,exacerbating the endoplasmic reticulum stress or encouraging the mitochondrial dysfunction.Identification of the pathological mechanisms underlying the GM-associated parkinsonism(GBA+PD)advances our understanding of PD.This review based on current literature aims to elucidate various genetic and clinical characteristics correlated with GBA mutations and to identify the numerous pathological processes underlying GBA+PD.We also delineate the therapeutic strategies to interfere with the mutant GCase function for further improvement of the related asynuclein-GCase crosstalks.Moreover,the various therapeutic approaches such as gene therapy,chaperone proteins,and histone deacetylase inhibitors for the treatment of GBA+PD are discussed.

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations:lessons from recent clinical trials

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifically,we discussed randomized clinical trials in subjects with Alzheimer's disease,Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations,and glucocerebrosidase-associated Parkinson's disease.Learning potential lessons to improve future therapeutic approaches is the aim of this review.Two long-term,controlled trials on three anti-β-amyloid monoclonal antibodies(solanezumab,gantenerumab and crenezumab)in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits.A major trial on tominersen,an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease,was prematurely interrupted because the drug failed to show higher efficacy than placebo and,at highest doses,led to worsened outcomes.A 28-week trial of tofersen,an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy.A trial of venglustat,a potent and brain-penetrant glucosylceramide synthase inhibitor,in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo.We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies,antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.

The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease

Gaucher disease（GD）,the commonest lysosomal storage disorder,results from the lack or functional deficiency of glucocerebrosidase（GCase） secondary to mutations in the GBA1 gene.There is an established association between GBA1 mutations and Parkinson＇s disease（PD）,and indeed GBA1 mutations are now considered to be the greatest genetic risk factor for PD.Impaired lysosomal-autophagic degradation of cellular proteins,including α-synuclein（α-syn）,is implicated in the pathogenesis of PD,and there is increasing evidence for this also in GD and GBA1-PD.Indeed we have recently shown in a Drosophila model lacking neuronal GCase,that there are clear lysosomal-autophagic defects in association with synaptic loss and neurodegeneration.In addition,we demonstrated alterations in mechanistic target of rapamycin complex 1（mTORC1） signaling and functional rescue of the lifespan,locomotor defects and hypersensitivity to oxidative stress on treatment of GCase-deficient flies with the mT OR inhibitor rapamycin.Moreover,a number of other recent studies have shown autophagy-lysosomal system（ALS） dysfunction,with specific defects in both chaperone-mediated autophagy（CMA）,as well as macroautophagy,in GD and GBA1-PD model systems.Lastly we discuss the possible therapeutic benefits of inhibiting mT OR using drugs such as rapamycin to reverse the autophagy defects in GD and PD.

Gaucher disease in Montenegro-genotype/phenotype correlations:Five cases report

BACKGROUND The most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the deposition of glucocerebroside in macrophage-monocyte system cells. The report targets clinical phenotypes of GD in order to correlate them with GBA gene mutations, as well as to identify GBA gene mutation in patients in Montenegro that are diagnosed with GD. CASES SUMMARY Five patients (4 male, 1 female) of type 1 GD (GD1) are reported. The age at diagnosis ranged from 7 to 40. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of splenomegaly and thrombocytopenia, while other symptoms included bone pain, hepatomegaly, abdominal pain and fatigue. Osteopenia was present in a majority of the patients: 4/5. All patients were found to have an asymptomatic Erlenmeyer flask deformity of the distal femur. On enzyme replacement therapy (ERT), the hematological and visceral parameters showed significant improvement, but no significant progression in bone mineral density was noticed. GBA gene sequencing revealed homozygosity for the N370S mutation in one patient. The genotypes of the other patients were N370S/55bp deletion, N370S/D409H (2 patients), and H255Q/N370S (1 patient). CONCLUSION The phenotypes of the GD1 encountered in Montenegro were severe but all responded well to ERT.

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system,acting to mediate excitatory neurotransmission.However,high levels of glutamatergic input elicit excitotoxicity,contribut-ing to neuronal cell death following acute brain injuries such as stroke and trauma.While excitotoxic cell death has also been implicated in some neurodegenerative disease models,the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration.Nevertheless,it is clear that excitatory synaptic dysregula-tion contributes to neurodegeneration,as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists.Here,we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease,Alzheimer’s disease,amyotrophic lateral sclerosis and Huntington’s disease.In contrast to classic excitotoxicity,emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration.We discuss mechanisms that regulate mitochondrial calcium uptake and release,the impact of LRRK2,PINK1,Parkin,beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters,and the role of autophagic mitochondrial loss in axodendritic shrinkage.Finally,we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix,thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss.While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems,a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.

Precision medicine in Parkinson's disease patients with LRRK2 and GBA risk variants-Let's get even more personal

Parkinson's disease(PD)is characterized by motor deficits and a wide variety of non-motor symptoms.The age of onset,rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation.Neuropathologically,the loss of substantia nigra dopaminergic neurons is a key feature of PD.The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions,but there is also great variability in the neuropathology between individuals.While the dopamine replacement therapies can reduce motor symptoms,current therapies do not modify the disease progression.Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification.It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials,and that it is unlikely that a single treatment will be effective in all patients.Precision medicine,using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD,has been suggested as a way forward.PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk.In this review we assess current clinical trials targeting two enzymes,leucine-rich repeat kinase 2(LRRK2)and glucocerebrosidase(GBA),which are encoded by two most common PD risk genes.Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood,we ask if these precision medicinebased intervention strategies will prove"precise"or"personalized"enough to modify the disease process in PD patients.We also consider at what phases of the disease that such strategies might be effective,in light of the genes being primarily associated with the risk of developing disease in the first place,and less clearly linked to the rate of disease progression.Finally,we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients,beyond those that actually carry risk variants of these genes.

Autophagy-lysosome pathway as a source of candidate biomarkers for Parkinson's disease

Parkinson's disease(PD)is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1%of the worldwide population.Diagnosis of PD relies on clinical history and physical examination,but misdiagnosis is common in early stages.Despite considerable progress in understanding PD pathophysiology,including genetic and biochemical causes,diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments.Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease-modifying treatments.Increasing evidence suggests that autophagic dysregulation causes the accumulation of abnormal proteins,such as aberrantα-synuclein,a protein critical to PD pathogenesis.Mutations in the GBA gene are a major PD risk factor andβ-glucocerebrosidase(GCase)is also emerging as an important molecule in PD pathogenesis.Consequently,proteins involved in the autophagy-lysosome pathway and GCase protein levels and activity are prime targets for the research and development of new PD biomarkers.The studies so far in PD biological material have yielded some consistent results,particularly regarding the levels of Hsc70,a component of the chaperone-mediated autophagy pathway,and the enzymatic activity of GCase in GBA mutation carriers.In the future,larger longitudinal studies,corroborating previous research on possible biomarker candidates,as well as extending the search for possible candidates for other lysosomal components,may yield more definitive results.