gaucher 
 disease ( gd ) is the most common lysosomal storage disorder and is caused by a deficiency in the enzyme glucocerebrosidase ( gcase ) . it is an autosomal recessive disorder that primarily affects the mononuclear phagocyte system by lipid accumulation ( tayebi et al . patients typically manifest hepatosplenomegaly , hematological changes , anemia and orthopedic complications ( grabowski 2008 ; choy and campbell 2011 ) . gd is classified into three types , on the basis of the presence or absence of neurological involvement : type 1 , the most common form , has no associated neurological symptoms ; type 2 , or acute neuronopathic disease , displays severe neurological involvement leading to death within the first years of life ; type 3 , or chronic neuronopathic gd , exhibits varying degrees of systemic involvement with at least one neurological manifestation ( hruska et al . the gene encoding gcase , gba , is located on chromosome 1q2122 and comprises 11 exons encoding a 497 amino acid protein . so far , about 300 mutations of this gene have been identified , including frame - shift , point and splice site mutations as well as deletions , insertions and recombinant alleles ( choy et al . 2007 ; hruska et al . 2008 ; choy and campbell 2011 ) . regarding the phenotype , null ,   mild  or  severe ,  depending on the resulting level of gcase production . null mutations , such as c.84dupg ( 84gg ) , do not lead to any enzyme production . mild mutations , such as c.1226a > g ( n370s ) , are only associated with type 1 disease . severe mutations , such as c.1448t > c ( l444p ) , result in enzyme production and are usually associated with type 2 or 3 disease ( beutler et al . 2005 ; campbell and choy 2012 ) . findings from more studies have shown that gba is an important risk factor for parkinson s disease ( pd ) . a small subset of gd patients with gba carriers developed parkinsonian symptoms including tremor , rigidity and bradykinesia ( bembi et al . 2003 ) and were also associated with diffuse lewy body ( lb ) pathology in the brain ( nishioka et al . this article reviews the present knowledge on the interaction of synuclein and gcase , with an emphasis on the pathogenesis and mechanism of gba - associated parkinsonism . parkinson s disease is the second most common neurodegenerative disorder , affecting 1  % of people over the age of 65 worldwide ( depaolo et al . it is generally diagnosed after the age of 60 and causes motor dysfunctions , such as bradykinesia , resting tremor , rigidity and postural instability , but also affects autonomic functions and cognition ( poewe 2008 ) . the two pathological features of pd are the death of neurons in certain regions of the brain and accumulation of proteins and lipids into structures . the former leads to the clinical picture of tremor , stiffness , slowness and difficulties with posture , and the latter generates lbs inside surviving neurons ( gai et al . these neuropathologic aggregates are also associated with other neurodegenerative disorders including dementia with lbs ( dlb ) and multiple system atrophy ( msa ) ( dev et al . the pathogenesis of pd is unknown , although age and neurotoxins are associated risk factors . in recent decades , several causative genes have been identified , including three missense mutations , a30p ( krger et al . 1998 ) , e46k ( zarranz et al . 2004 ) and a53 t ( polymeropoulos et al . 1997 ) of -syn , which is strongly associated with early - onset pd ( singleton et al . susceptibility studies suggest that contributing factors to pd include abnormal handling of misfolded proteins by the ubiquitin - proteasome system ( ups ) and autophagy - lysosomal pathway ( alp ) , increased oxidative stress , and mitochondrial , lysosomal and other pathogenic dysfunctions ( lesage and brice 2009 ) . multiple independent studies have reported the association between gba mutations and parkinsonism with an increased frequency of heterozygous gba mutations in various cohorts of patients with parkinsonism ( westbroek et al . furthermore , gba mutation carriers exhibit parkinsonian phenotypes and present a diffuse pattern of lb distribution in the cerebral cortex ( do rosrio almeida 2012 ) . the initial finding was that certain patients with gd exhibited parkinsonian symptoms and lb in the clinic , and additional reports were subsequently published ( bembi et al . 2003 ; singleton et al . 2003 ; chartier - harlin et al . 2004 ; westbroek et al . . mutations in the gba gene were identified as from 4 to 28  % in cases with pd and lb disorders ( goker - alpan et al . 2010 ; clark et al . 2005 ) . in 2003 , a group was assembled of 17 such individuals of various ethnicities , including ashkenazi jewish patients . the patients in this series had relatively mild gaucher manifestations with a mean age at diagnosis of 35  years ( tayebi et al . their parkinsonian manifestations were similar to those noted in sporadic parkinson s disease , although many had an age of onset in their 40s , and most were younger than that for sporadic pd , although not all responded favorably to levodopa . these individuals exhibited asymmetric tremor , rigidity , akinesia and , at times , dementia , showing that cognitive changes had also occurred . autopsies were carried out in the brain and showed lb inclusions , appearing gcase - positive on immunostains , with a more diffuse distribution involving in the cerebral cortex , hippocampus and brainstem / limbic regions ( nishioka et al . gba mutation carriers have diverse lb pathologies in brain regions and phenotypes compared to sporadic pd patients . it was noted that gd patients with parkinsonism frequently had relatives with parkinsonism who were heterozygous for gba mutations ( goker - alpan et al . in immunological analyses of brain tissue from gd patients and gd carriers with parkinsonism , all the samples with gba mutations showed lb pathology ( shachar et al . many other studies in different populations further support the link among gd , pd and lb disorders ( clark et al . 2008 ; kalinderi et al . 2009 ; sidransky et al . 2009 ; mitsui et al . 2009 ; lesage et al . 2010 ; mao et al . 2010 ) . a study of gba in 57 brain bank samples from subjects with pathologically confirmed pd demonstrated that 12  % carried a mutation , which was significantly higher than the mutation frequency even in the at - risk ashkenazi jewish population ( lwin et al . family studies revealed that among relatives of gaucher probands , there was an increased number of individuals affected with parkinsonism ( goker - alpan et al . importantly , several additional genetic studies in large patient cohorts demonstrated that patients with parkinsonism have an increased incidence of gba mutations . in 2009 , sidransky et al . published a study that consisted of a collective analysis of 5691 patients with pd , complemented by 4898 controls , from 16 centers and across 12 countries . the full gba coding region was screened , and loss - of - function mutations were observed in 6.9  % of cases and 1.3  % of controls . among the ashkenazi jewish subset , higher mutation frequencies were seen : 19.3  % in cases and 4.1  % in controls ( sidransky et al . subsequent studies indicated an increased incidence of pd in relatives of gd patients , many of whom were carriers of gba mutations ( goker - alpan et al . 2006 ) , making gba the most common known genetic risk factor for pd to date . furthermore , it is reported that non - motor symptoms ( nmss ) are more frequent in pd patients with heterozygous glucocerebrosidase mutations ( pd - gba ) ( brockmann et al . the overall nms score was higher for pd - gba than sporadic pd patients , and pd - gba patients showed more severe cognitive dysfunction , apathy , depression and anxiety ( mcneill et al . importantly , patients with gba - positive pd had significantly less precise memory compared to cases with gba - negative pd as well as gba - positive individuals without pd ( zokaei et al . meanwhile , among gd patients and heterozygous carriers , hyposmia , cognitive dysfunction and parkinsonian motor signs are prevalent . hyposmia is the most common prodromal marker , 10  % in gd patients and gba carriers , suggesting that hyposmia develops before cognitive dysfunction or motor abnormalities ( mcneill et al . hyposmia also occurs in lbd , in which olfactory dysfunction in lbd and pd is associated with lb deposition in the olfactory bulb , nucleus and cortex ( williams et al . it proposes that hyposmia may be the most sensitive , but not a specific marker for identifying gd patients and carriers at greatest risk of developing pd . the mechanisms underlying the relation between gba mutations and the development of parkinson s disease remain elusive . however , recent studies provide some new perspectives . generally , in autosomal recessive forms of parkinson s disease , such as those involving park2 , dj-1 and pink1 , loss - of - function mutations are implicated , and these patients have an early onset of disease manifestation . by contrast , gain - of - function mutations , for example those in scna and lrrk2 , are usually associated with autosomal dominant forms of parkinson s disease ( hardy et al . the recognition of the link among gba mutants , gcase activity , snca and pd has made an important contribution to our thinking on the pathogenetic pathways in pd and dementia with lbs ( lwin et al . support for gain - of - function mutations in gba is mainly from the following findings . most gba mutations are missense mutations , which result in a misfolded protein . in keeping with this is the finding that mutant gcase is present within a significant proportion of -syn inclusions in pd and gd brains ( sardi et al . 2011 , 2013 ) , suggesting that this abnormal conformation could contribute to the development of parkinsonism by increasing -syn aggregation or directly interfering with the cellular autophagic - lysosomal mechanisms that mediate -syn degradation ( cuervo et al . 2004 ) . furthermore , mutant gcase can accumulate in the endoplasmic reticulum , overwhelming the ubiquitin - proteasome pathway , burdening the lysosomal system or causing impairment of autophagy . some gba mutations encountered in patients with parkinsonism are null mutations  a finding in conflict with the gain - of - function hypothesis . in fact , carriers of null alleles might have an even higher risk of developing parkinsonism ( neumann et al . the potential role of lipid homoeostasis in causing parkinson s disease is a topic of great interest . parkinsonism could arise as a consequence of gcase deficiency because of the loss of function of the enzyme . -syn can bind to the lipid raft - associated ganglioside gm1s ( martinez et al . 2007 ; wei et al . 2009 ; yap et al . 2013 ) , so disordered glucosylceramide ( glccer ) metabolism is postulated to affect proper trafficking of -syn to presynaptic membranes or to directly affect its fibrillization , leading to an accumulation of toxic -syn species . hence , lipid storage could cause changes in lipid homoeostasis , with subsequent alterations in synuclein processing ( fortin et al . 2004 ; wei et al . 2009 ) . in gcase ko mice markers of neurodegeneration , p62/sqstm1 , ubiquitinated proteins and insoluble mitochondria were dysfunctional and fragmented , with impaired respiration and reduced respiratory chain complex activities . thus , a primary lysosomal defect causes accumulation of dysfunctional mitochondria as a result of impaired autophagy and dysfunctional proteasomal pathways ( osellame et al . gcase enzyme activity was reduced in the substantia nigra and cerebellum in sporadic pd brains , and gcase deficiency was significantly observed in pd with gba brain areas . for the most part , gcase protein expression was lower in pd with gba and pd brains , as well also decreased in sh - sy5y cells overexpressing -syn or with pten - induced putative kinase 1 ( pink1 ) deficiency ( gegg et al . 2012 ) . similar results were observed in fibroblasts from patients with gd and heterozygous mutation carriers with and without parkinson s disease compared with controls ( mcneill et al . the clinical finding that most patients with gd never develop parkinson s disease , despite low gcase activity , argues against a solely loss - of - function mechanism . this theory is supported by the low frequency of parkinson s disease reported in the large gaucher cohort in the international collaborative gaucher group ( icgg ) gaucher registry ( rosenbloom et al . thus , in most cases , the enzymatic deficiency can not predict parkinson s disease . -syn , a kind of presynaptic protein , is widely recognized for its role in pd . findings from recent studies have further suggested that -syn is involved in the pathogenesis of gba - associated parkinsonism . in the early stages of parkinson s disease , gcase deficits in sporadic parkinson s disease are related to the abnormal accumulation of -syn ( murphy et al . recently , a selective interaction between -syn and gcase was determined ( yap et al . 2011 ) . the interaction occurred under lysosomal solution conditions ( ph 5.5 ) , and no significant interaction was noted at ph 7.4 . residue level mapping showed that the interaction site was at the -syn c - terminal residues , 118137 . immunoprecipitation and immunofluorescence studies verified this interaction in human tissue and neuronal cell culture , respectively . intriguingly , the n370s mutant form of gcase has a reduced affinity for -syn , so this binding at lysosomal ph might play an important role in facilitating -syn degradation or preventing aggregation . much of the processing of -syn occurs in the cytoplasm , where this interaction was unexpected , but it offers a possibility for lysosomal pathways in -syn degradation . when gba is mutated or absent , the beneficial role of the interaction in -syn processing is disrupted . these findings suggest that the -syn - gcase association is favored in the lysosome and that understanding this noncovalent interaction provides the groundwork to explore molecular mechanisms linking pd with mutant gba alleles . studied the association between -syn pathology and gcase from a different perspective ( mazzulli et al . 2011 ) . they performed a small hairpin rna ( shrna)-mediated knockdown of gcase by lentiviral infection , which resulted in a 50  % reduction in gcase protein levels . reduced concentrations of endoglycosidase h - resistant gcase were also reported , ascribed to the depletion of the lysosomal form of the enzyme . gcase knockdown increased the steady - state levels of -syn 1.8-fold relative to controls , while the levels of tau , another disease - associated aggregation - prone protein , did not change . the same group then analyzed the dopaminergic neurons that were generated from induced pluripotent stem cells made from reprogrammed fibroblasts of a patient with gd . the results showed that these neurons also had an accumulation of -syn that resulted in neurotoxicity attributed to aggregation - dependent mechanisms . by working with a mouse model and human brain samples , they concluded that intracellular glccer levels control the formation of soluble toxic -syn oligomers and fibrils in cultured neurons , and mouse and human brain , leading to neurodegeneration . the promoted formation of -syn assemblies further contributes to a pathogenic cycle by inhibiting the lysosomal maturation and activity of normal gcase , resulting in additional glccer accumulation and elevated -syn oligomer formation . however , studies of brain samples indicate that aggregation of -syn is not related to gcase deficiency alone . proteins extracted from cerebral cortex samples from patients with synucleinopathies with and without gba mutations , as well as samples from control individuals and patients with gd , were studied by western blotting . patients with gba - associated parkinsonism showed aggregated oligomeric forms of -syn in the insoluble fraction , whereas only monomeric -syn was noted in patients with gba mutations without parkinsonism , including samples from patients with neuropathic gd ( choi et al . 2011 ) . recent evidence in saccharomyces cerevisiae and cell lines indicates that overexpression of -syn has the ability to block endoplasmic reticulum - golgi trafficking of proteins by inhibiting the formation of soluble n - ethylmaleimide - sensitive factor attachment protein receptor ( snare ) protein complexes ( cooper et al . furthermore , mazzulli et al . used primary cortical neurons to demonstrate that overexpression of either wild - type or a53t - mutant -syn resulted in retention of gcase in the er , associated with reduced lysosomal gcase activity ( mazzulli et al . 2011 ) . they then confirmed this in vitro by studying gcase glycosylation patterns in pd and healthy control brain tissue . in addition , the same group analyzed human cortical material by gcase western blot and showed that normal variation of -syn protein levels modulates the lysosomal maturation and activity of gcase in vivo . taken together , these data suggest that elevated levels of -syn observed in pd and other synucleinopathies leads to decreased lysosomal activity of normal gcase ( mazzulli et al . support for gain - of - function mutations in gba is mainly from the following findings . most gba mutations are missense mutations , which result in a misfolded protein . in keeping with this is the finding that mutant gcase is present within a significant proportion of -syn inclusions in pd and gd brains ( sardi et al . 2011 , 2013 ) , suggesting that this abnormal conformation could contribute to the development of parkinsonism by increasing -syn aggregation or directly interfering with the cellular autophagic - lysosomal mechanisms that mediate -syn degradation ( cuervo et al . 2004 ) . furthermore , mutant gcase can accumulate in the endoplasmic reticulum , overwhelming the ubiquitin - proteasome pathway , burdening the lysosomal system or causing impairment of autophagy . some gba mutations encountered in patients with parkinsonism are null mutations  a finding in conflict with the gain - of - function hypothesis . in fact , carriers of null alleles might have an even higher risk of developing parkinsonism ( neumann et al . the potential role of lipid homoeostasis in causing parkinson s disease is a topic of great interest . parkinsonism could arise as a consequence of gcase deficiency because of the loss of function of the enzyme . -syn can bind to the lipid raft - associated ganglioside gm1s ( martinez et al . 2007 ; wei et al . 2009 ; yap et al . 2013 ) , so disordered glucosylceramide ( glccer ) metabolism is postulated to affect proper trafficking of -syn to presynaptic membranes or to directly affect its fibrillization , leading to an accumulation of toxic -syn species . hence , lipid storage could cause changes in lipid homoeostasis , with subsequent alterations in synuclein processing ( fortin et al . 2009 ) . in gcase ko mice markers of neurodegeneration , p62/sqstm1 , ubiquitinated proteins and insoluble mitochondria were dysfunctional and fragmented , with impaired respiration and reduced respiratory chain complex activities . thus , a primary lysosomal defect causes accumulation of dysfunctional mitochondria as a result of impaired autophagy and dysfunctional proteasomal pathways ( osellame et al . gcase enzyme activity was reduced in the substantia nigra and cerebellum in sporadic pd brains , and gcase deficiency was significantly observed in pd with gba brain areas . for the most part , gcase protein expression was lower in pd with gba and pd brains , as well also decreased in sh - sy5y cells overexpressing -syn or with pten - induced putative kinase 1 ( pink1 ) deficiency ( gegg et al . 2012 ) . similar results were observed in fibroblasts from patients with gd and heterozygous mutation carriers with and without parkinson s disease compared with controls ( mcneill et al . the clinical finding that most patients with gd never develop parkinson s disease , despite low gcase activity , argues against a solely loss - of - function mechanism . this theory is supported by the low frequency of parkinson s disease reported in the large gaucher cohort in the international collaborative gaucher group ( icgg ) gaucher registry ( rosenbloom et al . thus , in most cases , the enzymatic deficiency can not predict parkinson s disease . -syn , a kind of presynaptic protein , is widely recognized for its role in pd . findings from recent studies have further suggested that -syn is involved in the pathogenesis of gba - associated parkinsonism . in the early stages of parkinson s disease , gcase deficits in sporadic parkinson s disease are related to the abnormal accumulation of -syn ( murphy et al . recently , a selective interaction between -syn and gcase was determined ( yap et al . 2011 ) . the interaction occurred under lysosomal solution conditions ( ph 5.5 ) , and no significant interaction was noted at ph 7.4 . residue level mapping showed that the interaction site was at the -syn c - terminal residues , 118137 . immunoprecipitation and immunofluorescence studies verified this interaction in human tissue and neuronal cell culture , respectively . intriguingly , the n370s mutant form of gcase has a reduced affinity for -syn , so this binding at lysosomal ph might play an important role in facilitating -syn degradation or preventing aggregation . much of the processing of -syn occurs in the cytoplasm , where this interaction was unexpected , but it offers a possibility for lysosomal pathways in -syn degradation . when gba is mutated or absent , the beneficial role of the interaction in -syn processing is disrupted . these findings suggest that the -syn - gcase association is favored in the lysosome and that understanding this noncovalent interaction provides the groundwork to explore molecular mechanisms linking pd with mutant gba alleles . studied the association between -syn pathology and gcase from a different perspective ( mazzulli et al . 2011 ) . they performed a small hairpin rna ( shrna)-mediated knockdown of gcase by lentiviral infection , which resulted in a 50  % reduction in gcase protein levels . reduced concentrations of endoglycosidase h - resistant gcase were also reported , ascribed to the depletion of the lysosomal form of the enzyme . gcase knockdown increased the steady - state levels of -syn 1.8-fold relative to controls , while the levels of tau , another disease - associated aggregation - prone protein , did not change . the same group then analyzed the dopaminergic neurons that were generated from induced pluripotent stem cells made from reprogrammed fibroblasts of a patient with gd . the results showed that these neurons also had an accumulation of -syn that resulted in neurotoxicity attributed to aggregation - dependent mechanisms . by working with a mouse model and human brain samples , they concluded that intracellular glccer levels control the formation of soluble toxic -syn oligomers and fibrils in cultured neurons , and mouse and human brain , leading to neurodegeneration . the promoted formation of -syn assemblies further contributes to a pathogenic cycle by inhibiting the lysosomal maturation and activity of normal gcase , resulting in additional glccer accumulation and elevated -syn oligomer formation . however , studies of brain samples indicate that aggregation of -syn is not related to gcase deficiency alone . proteins extracted from cerebral cortex samples from patients with synucleinopathies with and without gba mutations , as well as samples from control individuals and patients with gd , were studied by western blotting . patients with gba - associated parkinsonism showed aggregated oligomeric forms of -syn in the insoluble fraction , whereas only monomeric -syn was noted in patients with gba mutations without parkinsonism , including samples from patients with neuropathic gd ( choi et al . 2011 ) . recent evidence in saccharomyces cerevisiae and cell lines indicates that overexpression of -syn has the ability to block endoplasmic reticulum - golgi trafficking of proteins by inhibiting the formation of soluble n - ethylmaleimide - sensitive factor attachment protein receptor ( snare ) protein complexes ( cooper et al . furthermore , mazzulli et al . used primary cortical neurons to demonstrate that overexpression of either wild - type or a53t - mutant -syn resulted in retention of gcase in the er , associated with reduced lysosomal gcase activity ( mazzulli et al . 2011 ) . they then confirmed this in vitro by studying gcase glycosylation patterns in pd and healthy control brain tissue . in addition , the same group analyzed human cortical material by gcase western blot and showed that normal variation of -syn protein levels modulates the lysosomal maturation and activity of gcase in vivo . taken together , these data suggest that elevated levels of -syn observed in pd and other synucleinopathies leads to decreased lysosomal activity of normal gcase ( mazzulli et al . the proposed gain - of - function or loss - of - function mechanisms do not perfectly explain the association between pd and gd , and there are some clinical exceptions for each of them . therefore , the focus should be on the altered function of -syn in the observed association instead of a single gain or loss of function . a newly identified interaction between -syn and gcase was reported that might influence cellular levels of -syn by either promoting protein degradation and/or preventing aggregation ( sybertz and krainc 2014 ; yap et al . the authors also demonstrated that membrane - bound -syn interacted with gcase and that this complex formation inhibited enzyme function . the interaction of -syn and gcase in lysosomes may be beneficial to the degradation of -syn , while intracellular glccer levels control the formation of soluble toxic -syn oligomers and fibrils ( mazzulli et al . in other words , the interactions between -syn and gcase and between -syn and glccer have opposite effects on the aggregation of -syn . some gba mutations result in misfolded gcase , which has no activity but can still interact with -syn in lysosomes and contribute to the degradation . thus , the aggregation of -syn caused by glccer is compromised , which may explain why gd patients with low gcase activity will not develop parkinsonism . when gba mutations affect the interaction site , like n370s , the beneficial role of the interaction in -syn processing is disrupted , and the balance between aggregation and degradation is broken . this may be why carriers of null alleles might have an even higher risk of developing parkinsonism ( neumann et al . , if the aggregation of -syn can not be cleared , it will further inhibit the lysosomal maturation and gcase activity , resulting in additional glccer accumulation and elevated -syn . recent data show that increasing gcase activity with adeno - associated viral vector ( aav ) delivery of the enzyme into the brain of a gd mouse model can reduce the accumulation of snca , tau and ubiquitin ( sardi et al . 2013 ) . it suggested that increasing the glycosidase activity can modulate -syn processing and may modulate the progression of -synucleinopathies . in addition , neuronal glucosylceramide ( glccer ) accumulates to a certain threshold ; a series of second events is triggered , which includes neuroinflammation and neurodegeneration , then subsequently causes neuronal death ( farfel - becker et al . 2014 ) . hence , increasing the gcase activity in the cns represents a potential therapeutic strategy for gba - related and non - gba - associated synucleinopathies , including pd ( schapira and gegg 2013 ) . since a reduction of glucosylceramidase protein levels and activity occurs in the brain of gd and pd patients with gba mutation carriers , gcaes is a potential treatment target for gd therapy . ambroxol hydrochloride , a small molecule , reduces alpha - synuclein levels in overexpressing neuroblastoma cells and markers of oxidative and endoplasmic reticulum stress in cells bearing gcase mutations . ambroxol treatment results in a significant elevation of glucosylceramidase protein and activity levels in gd and pd with gba mutations by activating the coordinated lysosomal expression and regulation network ( mcneill et al . in addition , lysosomal activity of gc is tightly linked to expression of its trafficking receptor , the lysosomal integral membrane protein type-2 ( limp-2 ) , which acts as a chaperone helping to traffic glucosylceramidase from the endoplasmic reticulum to the lysosome ; therefore , manipulating limp-2 expression to increase lysosomal gc activity is also a promising strategy for the treatment of synucleinopathies and gba mutation carriers . heterologous expression of limp-2 accelerated clearance of overexpressed -synuclein and promoted autophagic / lysosomal function , possibly by increasing lysosomal gc activity ( rothaug et al . additionally , the receptor - interacting protein kinases ( ripks ) , a class of serine / threonine protein kinases , are directly involved in the pathway of pathological events in severe forms of gd . the significant extension of lifespan and improvements of motor coordination in ripk3 knockout mice support the notion that ripk3 is not only a key activator of necrotic cell death , but also the ripk3 pathway might be a molecular target for therapeutic intervention in gd ( vitner et al . further studies using techniques in cell biology , neuropathology and genetics are needed to better reveal the mechanisms that contribute to gba - associated parkinsonism . the role of -syn and gcase will continue to be a source of considerable interest in the field . elucidating the factors underlying this association is necessary to improve genetic counseling for people who carry mutations in this gene . moreover , a better understanding of the role of gcase in the development of parkinsonism will facilitate the development of new therapeutic strategies for gba - associated parkinsonism .